American Journal of Medical Genetics Part C (Semin. Med. Genet.) 121C:5 – 17 (2003)

A R T I C L E

Pediatric Medicine and the Genetic Disorders
of the Amish and Mennonite People
of Pennsylvania
D. HOLMES MORTON,* CAROLINE S. MORTON, KEVIN A. STRAUSS, DONNA L. ROBINSON,
ERIK G. PUFFENBERGER, CHRISTINE HENDRICKSON, AND RICHARD I. KELLEY

The Clinic for Special Children in Lancaster County, Pennsylvania, is a community-supported, nonprofit pediatric
medical practice for Amish and Mennonite children who have genetic disorders. Over a 14-year period, 1988–
2002, we have encountered 39 heritable disorders among the Amish and 23 among the Mennonites. We
emphasize early recognition and long-term medical care of children with genetic conditions. In the clinic
laboratory we perform amino acid analyses by high-performance liquid chromatography (HPLC), organic acid
analyses by gas chromatography/mass spectrometry (GC/MS), and molecular diagnoses and carrier tests by
polymerase chain reaction (PCR) amplification and sequencing or restriction digestion. Regional hospitals and
midwives routinely send whole-blood filter paper neonatal screens for tandem mass spectrometry and other
modern analytical methods to detect 14 of the metabolic disorders found in these populations as part of the
NeoGen Inc. Supplemental Newborn Screening Program (Pittsburgh, PA). Medical care based on disease
pathophysiology reduces morbidity, mortality, and costs for the majority of disorders. Among our patients who
are homozygous for the same mutation, differences in disease severity are not unusual. Clinical problems typically
arise from the interaction of the underlying genetic disorder with common infections, malnutrition, injuries, and
immune dysfunction that act through classical pathophysiological disease mechanisms to influence the natural
history of disease. � 2003 Wiley-Liss, Inc.

KEY WORDS: genetic diseases; general pediatric medical care; metabolic diseases; genotype-phenotype correlation

INTRODUCTION

Features of the Population

The manuscript of John A. Hostetler’s

book Amish Society was reviewed in

the early 1960’s for Johns Hopkins

University Press by Victor McKusick

[Hostetler, 1963]. McKusick recognized

the importance of the book as a socio-

logical study and realized the potential

of Amish populations for the study of

human genetics. McKusick’s review, and

the subsequent publication of Amish

Society in 1963, marked the beginning

of a collaboration between Hostetler and

McKusick that spanned several decades.

In 1978 McKusick edited and Johns

Hopkins Press published Medical Gene-

tic Studies of the Amish. [McKusick,

1978] Table I lists 26 genetic disorders

that were described in this publication,

which came from many different Amish

demes throughout Pennsylvania and the

midwest. Puffenberger and Francomano

discuss the origins of genetic studies in

the Mennonite and Amish populations

in accompaning articles [Francomano,

2003; Puffenberger, 2003].

Although these populations are

unique in many ways, when compared

to the general population of Pennsylva-

nia, the Amish and Mennonites are less

distinct than is generally appreciated. In

each of the 14 or more generations since

the early 1700s, 10 – 20% of the children

have left the Old Order communities

[Hostetler, 1993]. Lancaster County

church cemeteries, public school rosters,

and regional phone books include many

Amish and Mennonite family names.

Therefore, many so-called Amish alleles

D. Holmes Morton, M.D., Sc.D. (Hon.), is co-founder and director of the Clinic for Special
Children. He is a pediatrician with an interest in the influence of early diagnosis and treatment
upon the natural history and neurobiology of inherited metabolic disorders.

Caroline S. Morton, Ed. M., is co-founder and manager of the non-profit clinic and educational
organization called the Clinic for Special Children.

Kevin A. Strauss, M.D., is a pediatrician doing post-graduate studies at the Clinic focused upon
the neurobiology of genetic disorders and the pathophysiology of metabolic injuries of the brain.

Donna L. Robinson, R.N., C.N.P., is a pediatric intensive care nurse practitioner with special
interest in developing nursing protocols for management of hospitalized patients with metabolic
disorders.

Erik G. Puffenberger, Ph.D., is laboratory director at the Clinic for Special Children, with special
interest in molecular biology and population genetics.

Christine Hendrickson, RN, is a pediatric nurse who recently joined the Clinic staff to work with
children with genetic disorders in the outpatient setting.

Richard I. Kelley, M.D., Ph.D., is Associate Professor, Department of Pediatrics, Johns Hopkins
University, and member of the Division of Metabolism, Kennedy-Krieger Institute, Baltimore MD.
Dr. Kelley is consulting pediatrician and geneticist, and a founding board member, of the Clinic
for Special Children.

*Correspondence to: D. Holmes Morton, Clinic for Special Children, 535 Bunker Hill Rd.,
Strasburg, PA 17579.

DOI 10.1002/ajmg.c.20002

� 2003 Wiley-Liss, Inc.



or Mennonite alleles have diffused out

into the general population. The Old

Order Amish and Mennonite popula-

tions of Pennsylvania are new compared

to the time of origin of these gene muta-

tions. All three of the mutations causing

phenylketonuria (PKU) in the Old

Order Amish and Mennonites are found

throughout Europe. The so-called Amish

mutation for glutaric aciduria type 1

(GA1) is one of the more common

mutations found throughout Europe

and the United States [Biery et al.,

1996]. Therefore, for most disorders

found within the Amish and Menno-

nites, the alleles are not unique, but these

alleles are at different frequencies than in

the general population. The gene muta-

tions carried by the founders of the

demes of Pennsylvania are not distribut-

ed evenly, either within or among the

many subpopulations of the state. For 18

of the disorders seen regularly at the

clinic, the incidences are high, approxi-

mately 1/250 to 1/500 births. Although

there is a wide variety of heritable

disorders among the Plain people

(Table I), the majority of founder dis-

orders are clustered in a few families, and

the overall disease prevalence among

Plain people is relatively low. Examples

TABLE I. Metabolic Disorders and Syndromes Found in Medical Genetic Studies of the Amish [McKusick, 1978]

Inheritance OMIM Deme
b

Metabolic disorders
a

Phenylalanine hydroxylase deficiency AR 261600 IN/PA

Propionyl-CoA carboxylase deficiency AR 232000 OH/PA

Pyruvate kinase deficiency AR 266200 PA(B)

Syndromes

Albinism, oculocutaneous, tyrosinase deficient, type 1B AR 606952 IN

Spastic paraplegia AD PA(L)

Arthrogryposis, dysmelination, craniosynostosis, and

cleft palate

AR

Ataxia-telangiectasia AR 208900 IN

Brittle hair, intellectual impairment, and decreased

fertility

AR

Byler disease, progressive familiar intrahepatic cholestasis AR 216400 PA(Lw)

Cardiomyopathy, asymmetric sepal hypertrophy AD IN

Cardiomyopathy, nonobstructive AD OH

Cartilage-hair hypoplasia AR 250250 PA,OH,IN

Charcot-Marie-Tooth syndrome AR 118200

Coclear deafness, myopia, and intellectual impairment AR 221200 PA(L)

Jackson Weiss syndrome AD 123150 IN

Deafness, congenital AR

Ellis-van Creveld dwarfism AR 22550 PA(L)

Epidermolysis bullosa letalis AR 226700 OH

Familial manic-depressive illness AD 136800 PA(L)

Hypothyroidism and muscular hypertrophy

Limb girdle dystrophy, type 2E 604286 IN/PA

Mast syndrome AR 248900 OH(H)

McKusick-Kaufman syndrome AR 236700 OH/PA

Muscular dystrophy, limb-girdle type AR 253600 IN/PA

Nanophthalmos, familial AR 251600 NR

Oculocerebral syndrome with hypopigmentation AR 257800

Renal-retinal dysplasia AR 266900

Troyer syndrome AR 275900 OH(H)

Weill-Marchesani syndrome AR 277600 PA(L)

a
Disorders in italics are also entered in Tables II and III.

b
PA(B) is Belleville, PA; PA(L) is Lancaster county, PA; PA(Lw) is Lawrence county, PA, OH(H) is Holmes County, OH.

The gene mutations carried

by the founders of the demes

of Pennsylvania are not

distributed evenly, either

within or among the many

subpopulations of the state.

6 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE



of lower-frequency founder disorders

include PKU and medium-chain acyl

dehydrogenase deficiency (MCADD),

which are probably less common in the

Plain populations of Lancaster County

than in the general Caucasian popula-

tion. Some common genetic diseases

were apparently excluded by founder

sampling and/or genetic drift. For

example, cystic fibrosis is not seen in

the Plain people of Lancaster County

but is found in some other western

Pennsylvanian demes. This uneven dis-

tribution reflects different founders and

a 300-year separation of the various

subgroups prior to, and after, settlement

in North America. In the Plain people

of Pennsylvania, maple syrup urine

disease (MSUD) is found only in those

of Mennonite descent and GA1 is

found only in the Amish populations.

Although eight disorders are found in

both populations, only Crigler-Najjar

disease and propionic acidemia are

currently known to arise from the

same mutations in both populations.

MCADD, 3-methylcrotonylglycinuria

[Gibson et al., 1998], and at least two

forms of osteogenesis imperfecta are

found in both populations but are caused

by different mutations in the Amish and

Mennonites [Puffenberger, 2003].

MEDICAL CARE AND
THE CLINIC FOR
SPECIAL CHILDREN

The early genetic studies of the Plain

people indicated unique needs for the

medical care of people who were

geographically and culturally isolated.

The Clinic for Special Children was

organized to integrate general medical

care and modern genetics [Hostetler,

1993; Morton, 1994]. An initial goal

of the clinic founders was to diagnose

MSUD and GA1 in asymptomatic neo-

nates and prevent the metabolic crises in

order to prevent brain degeneration that

characterized these conditions. Because

common childhood infections often

provoke metabolic crisis in children with

these disorders, we reasoned that med-

ical care for affected children should be

directly provided by individuals who

were knowledgeable about the disor-

ders, who had laboratory facilities to

diagnose and monitor biochemical con-

trol during infectious illnesses, and who

were interested in general pediatric

practice [Morton et al., 1991; Morton,

1994; Morton et al., 2002b]. Because the

early symptoms of these serious disor-

ders are difficult to distinguish from

common diseases, we often evaluate

patients who turn out not to have a

genetic disorder common to the Plain

people. Infants who present with failure

to thrive and irritability or who become

unusually ill during otherwise common

infections most often do not have under-

lying genetic disorders. After the clinic

opened in 1989, it was apparent the

practice would not be limited to patients

with MSUD and GA1. The first ill

neonate sent to the clinic to rule out

MSUD did have a family history of

MSUD, but instead had Hirschsprung

disease with bowel obstruction and

sepsis. One of the more recently identi-

fied infants with MSUD also had a

second rare recessive disorder, severe

combined immune deficiency. Two of

our patients with MSUD have first

cousins with MCADD. Before 1988,

all Amish children with GA1 were said

to have cerebral palsy. Many children

with so-called Amish cerebral palsy did

have GA1, but others did not, and

their evaluations led to the descriptions

of troponin T1 myopathy [Johnston

et al., 2000], Amish lethal microcephaly

[Kelley et al., 2002; Rosenberg et al.,

2002; Strauss et al., 2002], and an auto-

somal recessive Pelizaeus-Merzbacher-

like central dysmyelination syndrome

[Morton et al., unpublished results]. We

recently evaluated a neonate with a

sibling with GA1 who fortunately did

not have GA1, but unfortunately, as we

learned from a neonatal screening test,

his hypospadias was a sign of another

recessive syndrome, 3-b hydroxyster-
oid dehydrogenase deficiency. Another

family has three children with GA1 and

a fourth with PKU. Over the years,

failure to thrive workups have led to the

diagnoses of Byler disease, three new

disorders of bile salt transport [Morton

et al., 2000], Bartter syndrome, aldoster-

one deficiency [Mitsuuchi et al., 1993],

and primary growth hormone defi-

ciency [Morton et al., 2002a]. Clearly,

the burden of genetic disease is high and

the need for specialized and compre-

hensive care is essential to the health of

the community. In the last 14 years we

Clearly, the burden of

genetic disease is high

and the need for specialized

and comprehensive care

is essential to the health

of the community.

have cared for patients from the Amish

and Mennonite populations with more

than 60 different single-gene disorders,

as shown in Tables II and III. These tables

summarize a clinical experience with

400 – 500 patients since 1988. Tables II

and III are not complete lists of genetic

disorders found in the Amish and

Mennonite populations of Pennsylvania.

However, we have seen patients from

other settlements in central and north-

western Pennsylvania where different

founder genes presumably explain the

prevalence of different sets of genetic

disorders.

CULTURAL AND
ECONOMIC BACKGROUND
OF THE CLINIC

The Clinic for Special Children was

registered in Pennsylvania as an inde-

pendent nonprofit organization in 1989.

The original board of directors included

three of the authors of this paper

(D.H.M., C.S.M., R.I.K.) and the late

Dr. John A. Hostetler, a descendant of

Amish parents and a sociologist of rural

culture. In 1990, several parents of

children with genetic disorders from

the Amish and Mennonite communities

joined the board. Both communities

were aware of significant numbers of

children with MSUD, GA1, and other

genetic disorders. The goal of these

parents was for the clinic to provide

comprehensive medical care for child-

ren with complex and unstable disor-

ders. The Clinic was viewed as a way to

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 7



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ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 9



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10 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE



allow the communities to care for their

own. This desire was in response to the

The goal of these parents

was for the clinic to

provide comprehensive

medical care for children

with complex and unstable

disorders, as a way to

allow the communities

to care for their own.

many difficulties encountered by the

Plain people in getting access to, and

paying for, specialized medical care.

The origins of community support and

the economic and medical impacts of the

clinic can be understood in relation to

the history of MSUD in the Mennonite

people. The collection of essays and let-

ters What Is Wrong with Our Baby?, com-

piled and published by John and Verna

Martin, parents of two MSUD children,

is an interesting and sometimes sobering

look at modern health care from a

parent’s perspective [Martin and Martin,

1995]. The oldest surviving Mennonite

patient with MSUD was born in 1967,

but many undiagnosed or untreated in-

fants died before she was born. She was in

a hospital in Philadelphia for 6 months,

did not regain her birth weight for

4 months, and today has severe disability

and retardation. Her sister, in whom

MSUD was recognized by 3 days of age,

became severely intoxicated, remained

hospitalized for many weeks, and also

has profound retardation.

FINANCIAL DIFFICULTIES
FOR PLAIN PEOPLE
IN TRADITIONAL
MEDICAL SETTINGS

Between 1966 and 1988, 36

Mennonite children were born with

MSUD. Over these 22 years, the

management of the neonates improved

and hospitalization times shortened.

However, as funding for research in

biochemical causes of mental retarda-

tion waned, the direct costs of care paid

by the Mennonite community in-

creased sharply. By 1988, the initial

care for a newly diagnosed neonate

with MSUD in regional pediatric hos-

pitals was $40,000 – $60,000 or more

[Morton et al., 2002b]. Amino acid

analyses cost $450, and when coupled

with physician charges and other testing

charges, the total cost of an outpa-

tient evaluation was typically $1,000 –

$1,500. These expenses were a major

difficulty for the Plain people, as they

historically have not participated in

medical insurance programs. Approxi-

mately half of the families contribute to

a form of major medical insurance

called Amish Aid or Mennonite Aid,

which is administered by businessmen

within the churches. Prior to the open-

ing of the clinic, benefit auctions were

held to help pay hospital bills of $50,000

or higher. Other church districts collect

alms to help families with large medical

bills. Members of the Old Orders are

not eligible for Medicare or Medicaid

benefits because of an exemption from

Social Security taxes. When young

adults join the Old Order Amish or

Mennonite churches, they sign an IRS

Form 4029, which indicates that they

are ‘‘a member of a religious body that is

conscientiously opposed to social secur-

ity benefits but that makes reasonable

provision for its own dependent mem-

bers’’ [Hostetler, 1993]. The exemption

from the tax also means that those who

sign IRS Form 4029 agree not to accept

money from state or federal programs

that are paid for by Social Security

funds. This cultural practice is one of

many issues community members face

when obtaining care for their children.

CHALLENGES IN
THE MEDICAL
MANAGEMENT OF
THESE DISORDERS

Earlier diagnosis and improved man-

agement did, in many cases, allow

normal growth and development, yet

several otherwise healthy children with

MSUD died unexpectedly from acute

cerebral edema after the newborn

period. Of the 36 children with MSUD

O
st

e
o
g
e
n
e
si

s
im

p
e
rf

e
c
ta

,
A

m
is
h

v
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t

þ
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ra

c
tu

re
s,

la
te

r
o
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se

t

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e
tt

sy
n
d
ro

m
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þ
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p
ic

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p
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e
m

ic
ro

c
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p
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al

y
in

fe
m

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s

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p
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ra

ti
c,

fu
ll

d
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ab
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ti
n
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p
ig

m
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n
to

sa
,

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fl
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,

se
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þ
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m

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ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 11



Earlier diagnosis and

improved management did,

in many cases, allow normal

growth and development,

yet several otherwise healthy

children with MSUD died

unexpectedly from acute

cerebral edema after

the newborn period.

born between 1966 and 1988, 14 (36%)

died of cerebral edema before the age of

10 years. The typical course of the

children was that they became ill with a

common infection, had poor appetite,

vomiting, and irritability, which pro-

gressed to lethargy, and then to coma. By

the time arrangements were made to

travel from Lancaster to the regional

hospital, the biochemical intoxication

was severe. Emergency efforts to reverse

the intoxication by intravenous fluids,

glucose, and dialysis failed, the cerebral

edema worsened, and within 24 hr after

entering the hospital, the child died of

brain stem herniation. Physicians and

parents knew that common infectious

illnesses provoked serious metabolic in-

toxication, but little was known about

how to control the metabolic response

to such illnesses in the outpatient set-

ting. Local services for children were

limited. Specialists and equipment that

were needed to study the early stages of

cerebral edema were in research labora-

tories far from the patients. The available

biochemical testing was of no utility for

the rapid treatment necessary to avert

cerebral edema because results took as

long as 2 weeks. Routine outpatient

visits to metabolic clinics in Philadelphia

could only be made on one afternoon

each week, and outpatient services to

assess acutely ill children were not avail-

able. Instead, ill children were referred to

emergency rooms, and the medical staff

of the ER usually knew less about the

management of MSUD than did the

child’s parents. Newborn screening for

MSUD was started by Pennsylvania in

1988, but the state-administered pro-

gram did not substantially improve mat-

ters for these patients. Until the Guthrie

method was replaced by the tandem

mass spectrometry program in 1993,

false positive rates were unacceptably

high [Morton et al., 2002b]. The state

program made no provisions to test and

provide immediate results for high-risk

infants. The three Mennonite infants

who were found by the state program

were 5 and 6 days old and already ill.

More important, the state follow-up

program made no provisions to pay for

the care of ill neonates, had no plans

for the assessment and care of acutely

ill older children, did not address the

problem of cerebral edema, and did not

support care for patients over the age

of 21 years. The state program did

offer to pay for several amino acid levels

per year and offered formula to those

who qualified for, and would accept,

Medicaid, but the program required

that Mennonite families obtain these

services at the hospitals in distant re-

gional centers.

In 1990, an amino acid analyzer

was given to the Clinic for Special

Children by two Mennonite churches.

To date, the clinic has performed

16,402 amino acid analyses on this

instrument. Because of our nonprofit

status and community support, we

were able to reduce the patient test

charge from $450 to $50. We also

decreased the analysis and reporting

time for plasma branched-chain amino

acids to 20 min, and we routinely

quantify plasma amino acids during an

outpatient clinic visit. Between 1989

and 2003, we managed 42 neonates

with MSUD. Twenty-one of these

neonates were from high-risk couples

recognized by family histories or carrier

tests, and the infants were tested for

MSUD and diagnosed before 24 hr of

age. With timely diagnosis, the neonates

were never ill and could be managed

without hospitalization. The diagnosis

of MSUD was made in 20 additional

neonates diagnosed because of clinical

illnesses; 3 of these infants were found

by the Pennsylvania screening pro-

gram. These 20 ill infants were managed

at Lancaster General Hospital by the

clinic staff and had a typical stay of 3 –

5 days with a hospital cost of $1,000 –

2,000 per patient per day. Over a 12-

year period, developmental outcomes

have been good [Morton et al., 2002].

We currently follow more than 70

patients with MSUD, most of whom

are of Mennonite descent. Between

1988 and 2002 we had 137 admissions

to our hospital for acute MSUD in-

toxication; however, the average an-

nual rate of hospitalization for our

MSUD patients is less than 1 day per

patient-year of follow-up. Between

1988 and 2002, there were, however,

no deaths from cerebral edema. The

current total annual formula cost for

our MSUD patients is about $115,000.

Again, most Mennonite families do not

accept formula or reimbursement for

costs from the Pennsylvania MSUD

follow-up program. The clinic pays half

of these costs for families who have

limited resources, and the families pay

the balance. The charge for an out-

patient visit is $35, and medical care

and laboratory testing are provided

at the clinic regardless of a family’s

ability to pay. In summary, a com-

prehensive health care system was

designed to provide sophisticated

medical care of patients with MSUD

within their community. By combining

community support and other dona-

tions with knowledgeable and sophisti-

cated laboratory and clinical care, the

morbidity, mortality, and costs have

been reduced.

CARE FOR PATIENTS
WITH DISORDERS
OTHER THAN MSUD

We believe that the cost of operat-

ing the Clinic for Special Children

could be fully justified if we cared for

no other patients than Mennonite

children with MSUD. However, the

medical and economic impacts of care

for patients with GA1, MCADD,

Crigler-Najjar disease, the bile salt

disorders, and many other disorders that

affect Amish and Mennonite children

provide equally compelling justification

for the clinic. More than 95% of the

disorders we see cause clinical problems

during infancy. Ten of the syndromes

12 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE



can be recognized by history and

physical examination, including the

common disorders, Amish lethal micro-

cephaly [Kelley et al., 2002; Strauss et al.,

2002], Swarey syndrome [Morton et al.,

unpublished results], a variant of cere-

bellar ataxia [Morton et al., unpublished

results], and a newly described syndrome

with infantile retinitis pigmentosa and

sensory ataxia [Higgins et al., 1999]. Five

disorders are primarily diagnosed by

amino acid analysis, and eight disorders

by organic acid analysis with gas chro-

matography/mass spectrometry (GC/

MS). Genomic DNA mutation analysis

is performed in the clinic [Puffenberger

and Morton, 2002; Puffenberger, 2003]

and is now used to diagnose 19 disorders,

including Byler disease and two other

disorders that disrupt bile salt transport,

Crigler-Najjar disease, fragile-X syn-

drome, glycogen storage disease type VI

[Chang et al., 1998], Amish osteogenesis

imperfecta, infantile spinal muscular

atrophy, and methylenetetrahydrofolate

reductase deficiency [Puffenberger and

Morton, 2002]. Two common lethal dis-

orders, troponin T1 myopathy [Johnston

et al., 2000] and infantile spinal muscular

atrophy, can be difficult to diagnose in a

newborn by examination, and we now

routinely confirm these diagnoses by

mutation analyses. Neonatal metabolic

screenings done by Neo Gen Inc.

identify using tandem mass spectrometry

routinely identify 14 of the disorders that

we see. The preliminary biochemical

diagnoses for most of these disorders is

confirmed in our laboratory on the

original specimen through polymerase

chain reaction (PCR)-based mutation

detection. The molecular basis of 17

disorders seen at the clinic remains to be

identified. Seven of these disorders

should yield to candidate gene sequenc-

ing, including GM1 gangliosidosis,

Bartter disease, and polycystic kidney

disease, whereas 10 syndromes without

candidate genes will require genome-

wide studies, including the cerebral

arteriovenous malformation syndrome,

manic depressive illness, several conge-

nital deafness syndromes, and a common

seizure/mental retardation syndrome.

THE IMPORTANCE OF
PRESYMPTOMATIC CARE

In our clinic, we have emphasized the

importance of diagnosis of asympto-

matic infants. For example, the diagnosis

of GA1 after degeneration of the basal

ganglia allows no opportunity for effec-

tive treatment [Morton et al., 1991;

Strauss and Morton, 2003a; Strauss et al.,

2003b]. The prospective management of

GA1 prevents basal ganglial degenera-

tion in at least 75% of cases. The clinical

importance of recognizing asympto-

matic infants with MCADD, propionic

acidemia, Crigler-Najjar disease, adrenal

insufficiencies, Bartter disease, the bile

salt transport disorders, and galactosemia

is readily apparent to a pediatrician

who has cared for infants with these

disorders who presented undiagnosed

and severely ill.

We have also found it helpful to be

able to immediately diagnose lethal

disorders in neonates. GM1 gangliosi-

dosis can be diagnosed by physical exam

and a single inexpensive test of urine

for increased urine oligosaccharide

excretion. Infantile spinal muscular atro-

phy and troponin T1 deficiency are both

routinely diagnosed in neonates by

molecular methods at a charge of less

than $50 [Puffenberger and Morton,

2002]. Because of easy access to the

clinic, prolonged hospitalizations invol-

ving multiple invasive and expensive

diagnostic tests for lethal disorders can

usually be avoided.

In the primary care setting, undiag-

nosed genetic syndromes present differ-

ently than in genetic clinics at referral

centers. Most often, the infants who are

seen at the clinic are irritable, feed

poorly, gain weight slowly, and in other

less well defined ways seem to the parents

to be ‘‘just not right.’’ Many teenage

patients and adults in these populations

with underlying genetic syndromes had

not been evaluated by modern diagnos-

tic methods. The first Mennonite girl

found to have MCADD at the clinic was

14 years old and had been hospitaliz-

ed several times because of vomiting and

ketotic hypoglycemia. Her sibling died

at age 6 months with hypoglycemia and a

fatty liver, which was diagnosed as Reye

syndrome in 1976.

Here and elsewhere, some genetic

disorders have been misdiagnosed as

child abuse. Approximately 10% of

patients with GA1 whom we have seen

were originally thought to be victims of

child abuse. Infants with GA1 may

present with subdural hemorrhages after

minor head trauma, because 75% of the

infants have open subdural and subar-

achnoid spaces that are crossed by bridg-

ing veins [Strauss and Morton, 2003a].

These intracranial hemorrhages are

usually large, and retinal hemorrhages

have developed spontaneously in asso-

ciation with large intracranial hemor-

rhages [Hymel et al., 2002]. In the

Amish population of Lancaster County,

we follow 28 children with three dif-

ferent hepatic bile salt transport disor-

ders. Nine of these infants (30%)

presented before 6 months of age with

bruising and bleeding secondary to

vitamin K deficiency. One such infant

presented in a coma with a full fontanel,

retinal hemorrhages, and bruising on

bony prominences. Shaken baby syn-

drome was the suspected diagnosis. The

infant was subsequently found to have

a vitamin K-responsive coagulopathy,

high serum bile salts, a deep, intracer-

ebral hemorrhage, and unilateral retinal

hemorrhages, which were atypical of

shaken baby syndrome. This infant and

her sibling are now known to be

homozygotes for a mutation in the tight

junction protein 2 gene [Carlton et al.,

2003]. Fractures caused by relatively

mild types of osteogenesis imperfecta

found in the Plain populations have also

been mistaken for child abuse.

THE UTILITY OF
A DETAILED
UNDERSTANDING
OF THE NATURAL
HISTORY OF DISEASE

We have had a unique opportunity to

observe the natural history of these

More than 95% of the

disorders we see cause clinical

problems during infancy.

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 13



disorders in many patients. The Men-

nonite variant of MSUD arises from a

stop codon in exon 1 of the BCKDHA

gene. Thus far, all Mennonite patients

have been homozygous for this mutation

and all have the classical form of the

disorder. In spite of the mutational

homogeneity, the phenotype ranges

from patients who are profoundly dis-

abled to those who are apparently

normal. Poor outcomes in patients with

MSUD can usually be understood in

terms of one or more of the following

problems: delays in neonatal diagnosis

and treatment, chronic essential amino

acid deficiencies, ineffective manage-

ment of metabolic intoxication during

infectious illnesses, and acute vascular

brain injuries caused by cerebral edema.

Neonates with MSUD who are diag-

nosed before 24 –36 hr of age are not ill,

and progressive metabolic intoxication

can be prevented by rational manage-

ment [Morton et al., 2002b]. Plasma

amino acid quantification allows diag-

nosis of the disorder as early as 12 hr of

age if high-performance liquid chroma-

tography (HPLC) or tandem mass spec-

trometry is used. It is important to note

that the Guthrie bacterial inhibition

assay is not sufficiently sensitive to be

used for specimens collected before

24 hr of age [Morton et al., 2002b]. All

infants with classical MSUD identified

by newborn screening programs will

be very ill if screening results are not

available before 4 days of age. Infants

identified and treated between 4 and 10

days of age can have good neurological

outcomes, but the cost of initial treat-

ment is higher than those diagnosed

within 24 hr. Neonatal screening pro-

grams for MSUD wherein specimens are

not collected until 72 hr of age and

results are not reported before 14 days of

age can expect high initial costs of

treatment and high morbidity and mor-

tality. After MSUD is diagnosed, the

prognosis for the patients depends on

several variables, including the time re-

quired to lower the plasma and tissue

leucine levels to normal, prevention of

the vascular compression and ischemic

injuries caused by critical brain edema,

and prevention of prolonged or severe

brain and systemic essential amino acid

deficiencies. Our impression is that

prolonged deficiencies of valine in the

brain during the critical period of rapid

brain growth between birth and 2 years

of age may be a major factor in mental

retardation seen in children with poorly

treated MSUD [Morton et al., 2002b].

The mainstay of therapy for MSUD

has been the dietary restriction of the

branched-chain amino acids. Unfortu-

nately, in many follow-up programs,

leucine levels are measured infrequently

and isoleucine, valine, and the other

essential amino acids are not monitored

at all. It is not possible to understand the

relationship of day-to-day metabolic

control and neurological outcome when

only a few plasma leucine levels are

measured per year. Intermittent changes

in tolerance related to normal variation

in growth velocity or illnesses will not be

appreciated. Deficiencies of branched-

chain amino acids and the unbalanced

transport of the other neutral amino

acids that compete with leucine for

entry into the brain cannot be assessed

by isolated measurements of leucine.

The effects of dietary therapy on intel-

lectual outcome can only be understood

by reference to the cumulative effects

of amino acid metabolism throughout

the critical period of brain growth

and development. In recent years, we

have monitored blood amino acid

levels in rapidly growing infants twice

weekly and gained an appreciation of

how quickly amino acid concentrat-

ions change, especially during otherwise

minor infectious illnesses.

Over a 13-year period, we have

admitted patients with MSUD to the

hospital for management of metabolic

crisis 137 times. More than 120 of these

admissions were necessary because of

catabolic intoxication caused by infec-

tious illnesses such as gastroenteritis,

otitis media, streptococcal pharyngitis,

sinusitis, and pulmonary infections.

Appendicitis, cholecystitis, torsion and

infarction of the ovary, and fractures also

cause metabolic crises. In addition, we

have 100 – 200 MSUD outpatient visits

per year to manage infectious illnesses

and other stressors. These illnesses cause

significant metabolic changes in patients

with MSUD and require one or more

measurements of plasma amino acids and

changes to a different treatment regimen

to prevent prolonged or progressive

metabolic intoxication. The ultimate

impact of these illnesses on clinical out-

come is influenced by the rapid avail-

ability of outpatient and inpatient

services, including amino acid analysis,

MSUD hyperalimentation solution, and

medical care by physicians and nurses

who have experience with the manage-

ment of the metabolic crisis and cerebral

edema.

MEDICAL CARE AND THE
OUTCOME OF OTHER
GENETIC DISORDERS

Eleven of the disorders that affect the

Amish and Mennonites are lethal or

invariably cause full disability. Although

these 11 disorders are lethal, affected

children may live months or years and

require many human and medical ser-

vices. The clinic routinely provides

medical care for children who have

lethal diseases. Most of these children

are cared for, and die, at home. Much of

the community support for the clinic

comes from families who need and

appreciate this care. The other 51 meta-

bolic disorders and syndromes present

with a range of clinical problems that

require timely diagnosis and ongoing

medical care. Our daily practice in-

cludes management of episodic crises

The ultimate impact of these

illnesses on clinical outcome

is influenced by the rapid

availability of outpatient

and inpatient services,

including amino acid analysis,

MSUD hyperalimentation

solution, and medical care by

physicians and nurses who

have experience with the

management of the metabolic

crisis and cerebral edema.

14 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE



in patients with the adrenal insufficiency

syndromes, Crigler-Najjar syndrome,

and various organic acidemias; and the

chronic malnutrition and fat-soluble

vitamin deficiencies of the bile salt

disorders, as well as the cardiac and

pulmonary problems of the patients with

Ellis-van Creveld syndrome and the

immune and gastrointestinal disorders

in patients with cartilage-hair hypopla-

sia. The early diagnosis of genetic

syndromes and anticipation of predict-

able problems is medically important

and often limits the adverse effects of

the disorder on the life of the patient,

especially for metabolic disorders, but

also for many other nonmetabolic

syndromes.

Immune deficiency states are

known to be associated with several of

the disorders that affect the Plain people.

In infants with cartilage-hair hypoplasia,

we have encountered severe varicella

infections, Pneumoncystis carinii pneumo-

nia, Hemophilus influenza meningitis in

an immunized 4-month-old, and persis-

tent parvovirus infection with a chronic

inflammatory disease similar to juve-

nile rheumatoid arthritis. Our young

patients with Ellis-van Creveld dwarfism

who have cardiac lesions and pulmonary

hypoplasia are particularly vulnerable to

infections with respiratory syncytial

virus. Our first encounter with the

Amish-Mennonite variant of pro-

pionic acidemia was an undiagnosed

12-month-old who presented with a

viral respiratory tract infection and

developed acute striatal necrosis and a

dilated cardiomyopathy with endo-

cardial fibroelastosis. Infants with the

Mennonite variant of nephrotic syn-

drome [Bolk et al., 1999] typically die

from the immune deficiency state caused

by the loss of immune globulins and

complement rather than from the loss of

albumin or renal failure. Gram-negative

sepsis must be anticipated in the ill

neonate with galactosemia or Hirsch-

sprung disease. Based on our experience

in Lancaster County, the practice of

medical genetics cannot be separated

from general pediatrics, and much of our

work in general pediatrics is focused

on the prevention and treatment of in-

fectious illnesses. The disease course of

many genetic disorders is directly deter-

mined by how effectively the interaction

of infectious disease and underlying

genetic disorder is understood and

managed.

BIOLOGY OF GENETIC
DISORDERS

Our daily clinical work within a

population with high incidences of

genetic diseases provides a unique

opportunity to study the biology of

genetic disorders. Because of the allelic

homogeneity of many disorders among

the Plain people, we observe a consis-

tent, or at least much more limited,

spectrum of variation at the primary

disease-causing locus than do most

physicians. These observations have

given us a different perspective on geno-

type-phenotype correlation. MSUD

exemplifies the complex relationship of

phenotype and genotype and, in addi-

tion, the manner in which health care

delivery affects clinical outcome. The

description of gene mutations is useful

for the diagnosis of many disorders, but

mutation analysis alone has seldom

provided us with insight into the phe-

notypic diversity that we encounter in

our patients who share the same disease

genotypes. Our understanding of varia-

tions in the natural history of genetic

disorders is more often based on the

concepts and language of cell biology,

pathophysiology, and critical periods of

brain development than on specific

molecular lesions. MSUD provides a

useful example of the complex relation-

ship between gene and disease. Descrip-

tions of mutations in branched-chain

keto-acid dehydrogenase as an under-

lying cause of MSUD do not help us

understand the multisystem regulators of

protein anabolism or catabolism that

cause marked changes in leucine toler-

ance. These perturbations of anabolism

and catabolism are more important

influences on day-to-day metabolic

control and illness than are the under-

lying mutations. Nor do the mutations

explain leucine-induced encephalopa-

thy, acute cerebral edema, or mental

retardation. The biology of MSUD can

only be understood in terms of the acute

and chronic effects of high blood and

tissue concentrations of leucine on

protein turnover in muscle and liver,

cell volume regulation, and brain amino

acid homeostasis as it relates to neuro-

transmitter function, and the devel-

opment and maintenance of brain

structure. MSUD arises from a complex

derangement of interorgan amino acid

transport.

Our impression is that scientists

who work as physicians and care for

several patients with the same genetic

disorder over long periods of time will

develop a different understanding of

genetic disease than scientists who study

disease mechanisms only in the labora-

tory. Laboratory scientists implicitly

assume that a genetic disease can be

adequately characterized by molecular,

enzymatic, biochemical, and cellular

experiments that are done at one point

in time and are independent of experi-

ence with an individual patient. Our

experience suggests that descriptions of

disease mechanisms based on in vitro

studies are necessarily incomplete and

may lead to an oversimplification of

models of genetic disorders. MSUD,

GA1, and the majority of the other

disorders managed at the clinic can only

be understood in terms of the patho-

physiological mechanisms that unfold in

individuals over significant periods of

time and in relationship to many dif-

ferent disease-causing factors, many of

which are not genetic in origin. For

GA1, MSUD, and PKU, the neurologi-

cal syndromes caused by single-gene

mutations arise from mechanisms of

injury and dysfunction that are linked

to critical periods of brain development.

In patients with GA1, episodes of

metabolic illness that cause acute striatal

necrosis in an infant are well tolerated in

the 6-year-old or adult. Unbalanced

amino transport that leads to mental

retardation in the infant with PKU and

MSUD causes attention deficit disorder,

mood disorders in older patients, and

presenile dementia in adults. The single-

gene mutations of MSUD and PKU give

rise to diseases by disruptions of complex

biological processes such as the meta-

bolic adaptations to fasts and illnesses,

cell volume regulation, brain amino acid

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 15



homeostasis, and postnatal organ growth

and development. Description of a

disease process without reference to such

biological processes and only by refer-

ence to point mutations in genes or

changes in enzyme activities seems to us,

as clinicians, to be inadequate. Assump-

tions about the nature of genetic disease

and the terms that are used to character-

ize these disorders influence how phy-

sician-scientists are trained and how,

throughout their careers, these scientists

ask and answer questions. A recent

editorial in the Journal of Clinical Investi-

gation indicated that research support in

the past 20 years has overwhelmingly

directed physician-scientists to the lab-

oratory and away from patients, showing

that 97% of physician-scientists who

received the Howard Hughes clinical

research awardees elected to do research

that did not involve patients [Goldstein

and Brown, 1997]. Our experiences at

the clinic over the past 14 years suggest

many important aspects of genetic dis-

eases will only become apparent to

physician-scientists who care for indivi-

dual patients over long periods and who

are interested in patients, pathophysiol-

ogy, and biology in the most general

sense.

CONCLUSIONS

The Clinic for Special Children was

established to provide care for Menno-

nite and Amish children in Lancaster

County who have MSUD and GA1.

However, the need for a similar ap-

proach to care for patients with other

disorders, in other places and popula-

tions, is increasingly apparent. Our

Mennonite patients with MSUD come

from every region of Pennsylvania,

Maryland, New York State, Kentucky,

Michigan, Wisconsin, Indiana, and Iowa.

GA1 is found in all Amish populations of

Pennsylvania and in northern New York

State. The most recent cases of GA1 we

have seen were recognized through the

supplemental screening program but

were not of Amish descent. In the

general population of the United States,

GA1 is now known to be one of the

more common inherited metabolic dis-

orders [Strauss and Morton, 2003].

Around the world, clusters of cases of

GA1 caused by founder genes have been

identified in Ireland, Spain, Israel, Saudi

Arabia, Chile, and two Native American

populations. Regardless of the under-

lying mutation, diagnosis and treatment

of MSUD and GA1 before the onset of

cerebral edema are essential. The med-

ical care of a patient with a genetic

disorder is no different than the care of a

patient with other problems that are

medically complex, such as diabetes

mellitus, manic depressive illness, leu-

kemia, congenital heart disease, renal

failure, rheumatoid arthritis, seizures,

congenital and acquired immune defi-

ciency syndromes, drug dependency,

and many other chronic medical trou-

bles. Rare genetic disorders are like the

majority of diseases treated by physi-

cians: few curable diseases exist. None-

theless, accessible and effective medical

care can limit suffering, improve func-

tion, reduce dependency, and otherwise

limit the effect of disease, genetic and

acquired, on the life of a patient. William

Osler said, ‘‘Such is our work.’’

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