Pediatric Medicine And The Genetic Disorders Of The Amish And

13 Pages·2003·0.13 MB·English

AmericanJournalofMedicalGeneticsPartC(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
TheClinicforSpecialChildreninLancasterCounty,Pennsylvania,isacommunity-supported,nonprofitpediatric
medicalpracticeforAmishandMennonitechildrenwhohavegeneticdisorders.Overa14-yearperiod,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
laboratoryweperformaminoacidanalysesbyhigh-performanceliquidchromatography(HPLC),organicacid
analyses by gas chromatography/mass spectrometry (GC/MS), and molecular diagnoses and carrier tests by
polymerasechainreaction(PCR)amplificationandsequencingorrestrictiondigestion.Regionalhospitalsand
midwivesroutinelysendwhole-bloodfilterpaperneonatalscreensfortandemmassspectrometryandother
modernanalyticalmethodstodetect14ofthemetabolicdisordersfoundinthesepopulationsaspartofthe
NeoGen Inc. Supplemental Newborn Screening Program (Pittsburgh, PA). Medical care based on disease
pathophysiologyreducesmorbidity,mortality,andcostsforthemajorityofdisorders.Amongourpatientswho
arehomozygousforthesamemutation,differencesindiseaseseverityarenotunusual.Clinicalproblemstypically
arisefromtheinteractionoftheunderlyinggeneticdisorderwithcommoninfections,malnutrition,injuries,and
immunedysfunctionthatactthroughclassicalpathophysiologicaldiseasemechanismstoinfluencethenatural
historyofdisease. (cid:1)2003Wiley-Liss,Inc.
KEYWORDS:geneticdiseases;generalpediatricmedicalcare;metabolicdiseases;genotype-phenotypecorrelation
INTRODUCTION [Hostetler,1963].McKusickrecognized McKusickthatspannedseveraldecades.
the importance of the book as a socio- In 1978 McKusick edited and Johns
Features ofthe Population logical study and realized the potential HopkinsPresspublishedMedicalGene-
of Amish populations for the study of tic Studies of the Amish. [McKusick,
The manuscript of John A. Hostetler’s humangenetics.McKusick’sreview,and 1978] Table I lists 26 genetic disorders
book Amish Society was reviewed in the subsequent publication of Amish that were described in this publication,
the early 1960’s for Johns Hopkins Society in 1963, marked the beginning whichcamefrommanydifferentAmish
University Press by Victor McKusick ofacollaborationbetweenHostetlerand demesthroughoutPennsylvaniaandthe
midwest.PuffenbergerandFrancomano
discuss the origins of genetic studies in
D. Holmes Morton, M.D., Sc.D. (Hon.), is co-founder and director of the Clinic for Special the Mennonite and Amish populations
Children.Heisapediatricianwithaninterestintheinfluenceofearlydiagnosisandtreatment
in accompaning articles [Francomano,
uponthenaturalhistoryandneurobiologyofinheritedmetabolicdisorders.
CarolineS.Morton,Ed.M.,isco-founderandmanagerofthenon-profitclinicandeducational 2003;Puffenberger,2003].
organizationcalledtheClinicforSpecialChildren. Although these populations are
KevinA.Strauss,M.D.,isapediatriciandoingpost-graduatestudiesattheClinicfocusedupon
unique in many ways, when compared
theneurobiologyofgeneticdisordersandthepathophysiologyofmetabolicinjuriesofthebrain.
DonnaL.Robinson,R.N.,C.N.P.,isapediatricintensivecarenursepractitionerwithspecial tothegeneralpopulationofPennsylva-
interestindevelopingnursingprotocolsformanagementofhospitalizedpatientswithmetabolic nia,theAmishandMennonitesareless
disorders.
distinctthanisgenerallyappreciated.In
ErikG.Puffenberger,Ph.D.,islaboratorydirectorattheClinicforSpecialChildren,withspecial
interestinmolecularbiologyandpopulationgenetics. eachofthe14ormoregenerationssince
ChristineHendrickson,RN,isapediatricnursewhorecentlyjoinedtheClinicstafftoworkwith theearly1700s,10–20%ofthechildren
childrenwithgeneticdisordersintheoutpatientsetting.
have left the Old Order communities
RichardI.Kelley,M.D.,Ph.D.,isAssociateProfessor,DepartmentofPediatrics,JohnsHopkins
University,andmemberoftheDivisionofMetabolism,Kennedy-KriegerInstitute,BaltimoreMD. [Hostetler, 1993]. Lancaster County
Dr.Kelleyisconsultingpediatricianandgeneticist,andafoundingboardmember,oftheClinic churchcemeteries,publicschoolrosters,
forSpecialChildren.
andregionalphonebooksincludemany
*Correspondence to: D. Holmes Morton, Clinic for Special Children, 535 Bunker Hill Rd.,
Strasburg,PA17579. Amish and Mennonite family names.
DOI10.1002/ajmg.c.20002 Therefore,manyso-calledAmishalleles
(cid:1) 2003 Wiley-Liss, Inc.
6 AMERICANJOURNALOFMEDICALGENETICS(SEMIN.MED.GENET.) ARTICLE
TABLE I. MetabolicDisordersandSyndromesFoundinMedicalGeneticStudiesoftheAmish[McKusick,1978]
Inheritance OMIM Demeb
Metabolicdisordersa
Phenylalaninehydroxylasedeficiency AR 261600 IN/PA
Propionyl-CoAcarboxylasedeficiency AR 232000 OH/PA
Pyruvatekinasedeficiency AR 266200 PA(B)
Syndromes
Albinism,oculocutaneous,tyrosinasedeficient,type1B AR 606952 IN
Spasticparaplegia AD PA(L)
Arthrogryposis,dysmelination,craniosynostosis,and AR
cleftpalate
Ataxia-telangiectasia AR 208900 IN
Brittlehair,intellectualimpairment,anddecreased AR
fertility
Bylerdisease,progressivefamiliarintrahepaticcholestasis AR 216400 PA(Lw)
Cardiomyopathy,asymmetricsepalhypertrophy AD IN
Cardiomyopathy,nonobstructive AD OH
Cartilage-hairhypoplasia AR 250250 PA,OH,IN
Charcot-Marie-Toothsyndrome AR 118200
Cocleardeafness,myopia,andintellectualimpairment AR 221200 PA(L)
JacksonWeisssyndrome AD 123150 IN
Deafness,congenital AR
Ellis-vanCrevelddwarfism AR 22550 PA(L)
Epidermolysisbullosaletalis AR 226700 OH
Familialmanic-depressiveillness AD 136800 PA(L)
Hypothyroidismandmuscularhypertrophy
Limbgirdledystrophy,type2E 604286 IN/PA
Mastsyndrome AR 248900 OH(H)
McKusick-Kaufmansyndrome AR 236700 OH/PA
Musculardystrophy,limb-girdletype AR 253600 IN/PA
Nanophthalmos,familial AR 251600 NR
Oculocerebralsyndromewithhypopigmentation AR 257800
Renal-retinaldysplasia AR 266900
Troyersyndrome AR 275900 OH(H)
Weill-Marchesanisyndrome AR 277600 PA(L)
aDisordersinitalicsarealsoenteredinTablesIIandIII.
bPA(B)isBelleville,PA;PA(L)isLancastercounty,PA;PA(Lw)isLawrencecounty,PA,OH(H)isHolmesCounty,OH.
or Mennonite alleles have diffused out found within the Amish and Menno- thegeneralpopulation.Thegenemuta-
into the general population. The Old nites,theallelesarenotunique,butthese tions carried by the founders of the
Order Amish and Mennonite popula- allelesareatdifferentfrequenciesthanin demesofPennsylvaniaarenotdistribut-
tionsofPennsylvaniaarenewcompared ed evenly, either within or among the
tothetimeoforiginofthesegenemuta- manysubpopulationsofthestate.For18
The gene mutations carried
tions.Allthreeofthemutationscausing of the disorders seen regularly at the
phenylketonuria (PKU) in the Old by the founders of the demes clinic,theincidencesarehigh,approxi-
OrderAmishandMennonitesarefound mately1/250to1/500births.Although
of Pennsylvania are not
throughoutEurope.Theso-calledAmish there is a wide variety of heritable
mutation for glutaric aciduria type 1 distributed evenly, either disorders among the Plain people
(GA1) is one of the more common (Table I), the majority of founder dis-
within or among the many
mutations found throughout Europe ordersareclusteredinafewfamilies,and
and the United States [Biery et al., subpopulations of the state. the overall disease prevalence among
1996]. Therefore, for most disorders Plain people is relativelylow.Examples
ARTICLE AMERICANJOURNALOFMEDICALGENETICS(SEMIN.MED.GENET.) 7
of lower-frequency founder disorders ders, who had laboratory facilities to ciency [Morton et al., 2002a]. Clearly,
include PKU and medium-chain acyl diagnoseandmonitorbiochemicalcon- theburdenofgeneticdiseaseishighand
dehydrogenase deficiency (MCADD), trolduringinfectiousillnesses,andwho the need for specialized and compre-
whichareprobablylesscommoninthe were interested in general pediatric hensivecareisessentialtothehealthof
Plain populations of Lancaster County practice [Morton et al., 1991; Morton, the community. In the last 14 years we
than in the general Caucasian popula- 1994;Mortonetal.,2002b].Becausethe
tion. Some common genetic diseases early symptoms of these serious disor-
were apparently excluded by founder ders are difficult to distinguish from Clearly, the burden of
sampling and/or genetic drift. For common diseases, we often evaluate genetic disease is high
example, cystic fibrosis is not seen in patients who turn out not to have a
and the need for specialized
the Plain people of Lancaster County genetic disorder common to the Plain
but is found in some other western people.Infantswhopresentwithfailure and comprehensive care
Pennsylvanian demes. Thisunevendis- tothriveandirritabilityorwhobecome
is essential to the health
tributionreflectsdifferentfoundersand unusuallyillduringotherwisecommon
a 300-year separation of the various infectionsmostoftendonothaveunder- of the community.
subgroupspriorto,andafter,settlement lying genetic disorders. After the clinic
in North America. In the Plain people opened in 1989, it was apparent the
of Pennsylvania, maple syrup urine practicewouldnotbelimitedtopatients have cared for patients from the Amish
disease (MSUD) is found only in those with MSUD and GA1. The first ill and Mennonite populations with more
of Mennonite descent and GA1 is neonate sent to the clinic to rule out than 60 different single-gene disorders,
found only in the Amish populations. MSUD did have a family history of asshowninTablesIIandIII.Thesetables
Although eight disorders are found in MSUD, but instead had Hirschsprung summarize a clinical experience with
both populations, only Crigler-Najjar disease with bowel obstruction and 400–500 patients since 1988. Tables II
disease and propionic acidemia are sepsis.Oneofthemorerecentlyidenti- andIIIarenotcompletelistsofgenetic
currently known to arise from the fied infants with MSUD also had a disorders found in the Amish and
same mutations in both populations. second rare recessive disorder, severe MennonitepopulationsofPennsylvania.
MCADD, 3-methylcrotonylglycinuria combined immune deficiency. Two of However, we have seen patients from
[Gibson et al., 1998], and at least two our patients with MSUD have first other settlements in central and north-
forms of osteogenesis imperfecta are cousins with MCADD. Before 1988, western Pennsylvania where different
foundinbothpopulationsbutarecaused all Amish children with GA1 weresaid founder genes presumably explain the
bydifferentmutationsintheAmishand to have cerebral palsy. Many children prevalence of different sets of genetic
Mennonites[Puffenberger,2003]. with so-called Amishcerebralpalsy did disorders.
have GA1, but others did not, and
theirevaluationsledtothedescriptions
MEDICAL CARE AND CULTURAL AND
of troponin T1 myopathy [Johnston
THE CLINIC FOR ECONOMIC BACKGROUND
etal.,2000],Amishlethalmicrocephaly
SPECIAL CHILDREN OF THE CLINIC
[Kelley et al., 2002; Rosenberg et al.,
The early genetic studies of the Plain 2002;Straussetal.,2002],andanauto- The Clinic for Special Children was
people indicated unique needs for the somal recessive Pelizaeus-Merzbacher- registered in Pennsylvania as an inde-
medical care of people who were like central dysmyelination syndrome pendentnonprofitorganizationin1989.
geographically and culturally isolated. [Mortonetal.,unpublishedresults].We Theoriginalboardofdirectorsincluded
The Clinic for Special Children was recently evaluated a neonate with a three of the authors of this paper
organized to integrate general medical sibling with GA1 who fortunately did (D.H.M., C.S.M., R.I.K.) and the late
care and modern genetics [Hostetler, nothaveGA1,butunfortunately,aswe Dr. John A. Hostetler, a descendant of
1993; Morton, 1994]. An initial goal learned from a neonatal screening test, Amishparentsandasociologistofrural
of the clinic founders was to diagnose his hypospadias was a sign of another culture. In 1990, several parents of
MSUDandGA1inasymptomaticneo- recessive syndrome, 3-b hydroxyster- children with genetic disorders from
natesandpreventthemetaboliccrisesin oid dehydrogenase deficiency. Another theAmishandMennonitecommunities
ordertopreventbraindegenerationthat familyhasthreechildrenwithGA1and joined the board. Both communities
characterizedtheseconditions.Because a fourth with PKU. Over the years, were aware of significant numbers of
common childhood infections often failuretothriveworkupshaveledtothe children with MSUD, GA1, and other
provokemetaboliccrisisinchildrenwith diagnoses of Byler disease, three new genetic disorders. The goal of these
these disorders, we reasoned that med- disorders of bile salt transport [Morton parents was for the clinic to provide
icalcareforaffectedchildrenshouldbe etal.,2000],Barttersyndrome,aldoster- comprehensive medical care for child-
directly provided by individuals who onedeficiency[Mitsuuchietal.,1993], ren with complex and unstable disor-
were knowledgeable about the disor- and primary growth hormone defi- ders.TheClinicwasviewedasawayto
8 AMERICANJOURNALOFMEDICALGENETICS(SEMIN.MED.GENET.) ARTICLE
Clinicalnotes MilroyAmish.Severecombinedimmunedeficiency.Lethalw/tbonemarrowtransplantNeonatalhyponatremia/hyperkalemia.Maleshave ambiguousgenitaliabutseverityvariablePoorgrowthininfancywithanorexiaandlowIGF-1andGH Poorgrowth,hyponatremia/hyperkalemia,variablephenotypeKernicterusw/tneonataldiagnosisandphototherapy.Lethalw/tlivertransplant CarriersofclassicalgeneidentifiedbyNeoGen.CommoninMarylandAmishBasalganglialdegenerationwithcerebralpalsy-like dystoniaLethal.FoundinMilroyAmishdemebutnotinLancasterCounty Rare.Highmorbidityandmortalityw/tneonatalscreenings.InfectioninducedcrisisMildphenotype,severalasymptomaticadultsandchildren Variablephenotype,severetomildhyperpheVariablePhenotype.Basalganglialinjury,cardiomyopathy CommoninBellevilledeme.Erthroblastosis,hepatopathyandhemolysisInfantsasymptomatic.Increasedbutyrylcarnitineand urineethylmalonateCoronaryarterydiseaseinchildhood.Highcholersterolandsitosterol CommoninLancasterAmish.Intracerebralhemorrhagesinallagegroups.DxbyMRAPoorgrowth,pruritis,vitaminK,andDdeficiencies ininfancyPoorgrowth,pruritis,vitaminK,andDdeficienciesininfancy.Lethalw/tlivertransplant
Diagnosedymutationadetection þ þ þ þ þ þ þ þþ þ þ þ þ
b
h
s
niaAmi acidsandarnitinesMS/MS þ þ þ þ þþ þ
a oc
sylv Aminacylby
n
n
Pe nicMS
of orgaC/
Disorders Urine(serum)oracidsbyG þ þ þ þ þ þþ þ þ
Genetic Serumminoacidanalysis þ
a
II. n
BLE NeogeorPAscreen þ þ þ þ þ þþ þ
A
T
y
Historandexam þ þ
Illnessduringinfancy þ þ þ þ þ þ þ þ þ þ þþ þ þ þ þ þ
etabolicdisorders Adenosinedeaminasedeficiency AdrenalhyperplasiaII3ß-hydroxysteroid dehydrogenasedef.Congenitalgrowthhormonedeficiency CorticosteronemethyloxidaseIIdef.Aldosteronedef.Crigler-Najjarsyndrometype1 Galactosemia,DuarteandDuarte/classicalvariantsGlutarylCoAdehydrogenasedeficiency GM1gangliosidosis,beta-galactosidasedeficiency Mediumchainacyl-CoAdehydrogenasedeficiency3-Methylcrotonyl-CoAcarboxylasedeficiency PhenylalaninehydroxylasedeficiencyPropionyl-CoAcarboxylasedeficiency Pyruvatekinasedeficiency Shortchainacyldehydrogenasedeficiency Sitosterolemia ndromesArterialvenousmalformationsyndrome Blanksyndrome,familiarhypercholanemia Bylerdisease,familiarintrahepaticcholestasis
M y
S
ARTICLE AMERICANJOURNALOFMEDICALGENETICS(SEMIN.MED.GENET.) 9
Variablephenotypeforgrowth,hair,immunedeficiency,andHirschsprungsdisease Grossmotorandlanguagedelays.AtaxiaandabnormalgaitvariableLethal.Typicalphenotype,infantileform.Seenin AmishinBellevilleareaCommoninLancaster.Lethalwithbrainmalformationsandprogressiveencephalopathy Severearrhythmias.Life-threateningcardiaceventsintheneonate.DxbyEKGRare,lethalsyndrome.Someinfantshaveectodactylyonly CommoninLancaster.Pulmonaryhypoplasia,cardiacdiseasein25–40%Presentsinyoungadultsasearlyglaucomaandcataracts FemaleinfertilitywithoutearlydetectionandrepairOnecaseinBellevilleAmish.Thechildalsohadpyruvatekinasedeficiency Beta-sarcoglycanglycoproteindefectUncommon.Twocaseswith:periobitalandfacialtumors;obstructivehydrocephalis Common.Dominantvariant.FractureslateronsetandosteoporosisOnsetrenalfailureage30–50years.Noliverdisease.Renaltransplant Typicalprogressivemicrocephalyinfemales.Sporatic,fulldisabilityAutosomalrecessivevariant.Congenitalnystagmus, motordelays.DxbyMRICommoninBellevillearea.Lethal.NotendocrinopathyorKennedysyndrome Common,lethal.Tremorsinuteroandatbirth.‘‘Chickenbreastdisease’’
þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ
3.
0
0
2
þ þ þ þ þ þ þ þþ þ þ þ þ þ er,
g
er
n b
Cartilage-hairhypoplasiadwarfism Cerebellarataxiawithpreservedreflexes Cockaynesyndrome Lethalmicrocephallywith2-ketoglutaricaciduria Congenitalsupraventriculararrhythmias Ectrodactyly,omphaloceleandcardiacmalformations Ellis-vanCrevelddwarfism Fuchsendothelialdystrophyofthecornea Mckusick-KauffmansyndromeMoyamoyadisease Musculardystrophy,limb-girdletypeNeurofibromatosis Osteogenesisimperfectawithopalescentteeth,fracturesPolycystickindeydisease,adulttype Rettsyndrome Riehlsyndrome,Pelizaeus-Merzbacher-like dysmylinationSwareysyndrome,fetalgonadalfailure,suddeninfantdeath Troponintype1myopathy,infantilenemalimyopathy GeneandmutationidentificationPuffen
a
10 AMERICANJOURNALOFMEDICALGENETICS(SEMIN.MED.GENET.) ARTICLE
onites Clinicalnotes Kernicterusw/tneonataldiagnosisandphototherapyLethalw/tlivertransplant Renalstonesinearlychildhoodwithriskofrenaldamage.Common.FourmutationsCommoninfamilieswithCrigler-NajjardiseaseHomozygotesforTATAboxpolymorphisms AbnormalliverenzymesandhighcholesterolIrritabilityandhepatomegalyafterweaning<ALC100/mm,nothymicshadoworT-lymph.Bonemarrow transplant.?IL7receptdefectClassicalMSD.Livertransplantwaseffectivetherapy,bonemarrowtransplantwasnot Highmorbidityandmortalitywithoutneonatalscreenings.InfectioninducedcrisisMildphenotype,severalasymptomaticadultsandchildren Neonataljaundice,erythoblastosis.CompoundheterozygoteVariablephenotype,mildhyperphetosevere SamemutationasAmish.VariablePhenotype Onecase,noclinicaldisease Childhoodonset,Israelimutation,onecase.DYT6reportedinmidwesternMenn.group Tumornecrosisfactorreceptormutationin1family.TRAPSandFMFgenesnlinanotherfamilyCommondisorder.VariablephenotypemakesclinicaldiagnosisdifficultHemolysis,hyperbilirubinemia,abnormalbloodsmear.RBCfragility testdiagnosticNeonatalbowelobstructionandsepsis.Polygenicdisease.Highlyvariablephenotype Edemaandinfections.Lethalw/trenaltransplantCongenitaldetachmentofretinaes.Fractures,lateonset.Unknownmutation
n
vaniaMen Diagnosedbymutationadetection þ þ þ þ þ þ þ þþ þ þ þ /þ(cid:1) þ /þ(cid:1) þ
yl
rofPenns Aminoacids andacylcarnitinesbyMS/MS þ þ þ þ þ þ
e
d
cDisor Urineor(serum) organicacidsbyGC/MS þ þ þ þþ þ þ
ti
e
III.Gen Serumor (urine)minoacidanalysis ()þ þ þ þ
a
E
L
B n
TA NeogeorPAscreen þ þ þ þ þ þ
y
Historandexam þ þ þ þ þ þ þ
Illnessduringinfancy þ þ þ þ þ þ þþ þ þ þ þ þþ
MetabolicdisordersCrigler-Najjarsyndrometype1 Cystinuria Gilbertsyndrome Glycogenstoragedisease,type6 Immunedeficiency,SCIDvariant Branchedchain2-ketoaciddehydrogenasedeficiency Mediumchainacyl-CoAdehydrogenasedeficiency3-methylcrotonyl-CoAcarboxylasedeficiency MevalonatekinasedeficiencyPhenylalaninehydroxylasedeficiency Propionyl-CoAcarboxylasedeficiencyTyrosinemiatype3 yndromesDystoniasDYT-1 Familialperiodicfever(TRAPS) FragilexsyndromeHereditaryspherocytosis Hirschsprungdisease Nephroticsyndrome,congenitalOsteogenesisimperfecta,detachedretinaes
S
ARTICLE AMERICANJOURNALOFMEDICALGENETICS(SEMIN.MED.GENET.) 11
allowthecommunitiestocarefor their tionwaned,thedirectcostsofcarepaid
own.Thisdesirewasinresponsetothe by the Mennonite community in-
malesSporatic,fulldisability dto1q31-32.Nomutationin on.Amilderclinicalvarianthas oodonsetdoesoccur.Mutation wTmipthehrwedocaivgocsioamdafleolpcrcaoloetfrxmhetehfapoecnrrslediehcnhuepincinalsrsdtieotrvaneebntsle ccwp[awcMnhariiietraattaeaohhlrlysgsrepsMtfeedoowhss,nrySascsUshtiaoehcaDs$tiertan4pnaei$0ltnlyw4oc,..0,h5trl0aeya0B2l0gr,0gyi–dcao0eo$in2sna16sdbaga9t0nln]8w,.dpoo08ehsf0oA,ede0tmdahtinahneoitecnnrrroiooetceiuoumnshpntatipoiotclaneiaritsaddgee--l
fe pe eti dh tient evaluation was typically $1,000–
Fractures,lateronset Typicalprogressivemicrocephalyin Commonsyndrome.AXPC1,MapPlexinA2.UnknownmutationCommon,lethalSMN1exon7del beenseeninonefamilyVariablephenotype,common.Chilunknown mPpTalhaaynieinnyogaprdtdlieoiglifosofoifinocprwca,slreudrotslefetiphnirceefesooscg,imrcaeeoaltmnittzmshicenuoeadgmnuiirnwtaumytcoeancesrweuydiesptdinscitpaeo.toblsory,tcaaatnnrhedde. $dhmmacwwa1iihifasel,tffiltt5dioheoecc0idrirlhcunym0ialcA.ttilhayshTmaliolenalyffhfdioscsuoemhrhhmsfrueatiatAnhrnahvcejieceeioshxdetrfPepeansporelm.aeomrnriPdotinslerMgeibidesrppoaysieaecrwmncroabttoenlopsiurc.nolestieitnAiphnr,niaiaepsteabutepossemursrdpatmtAoaehnexjienecotidinonye--r,
ingof the clinic, benefit auctionswere
theeconomicandmedicalimpactsofthe
heldtohelppayhospitalbillsof$50,000
clinic can be understood in relation to
þ orhigher.Otherchurchdistrictscollect
thehistoryofMSUDintheMennonite
almstohelpfamilieswithlargemedical
people.Thecollectionofessaysandlet-
bills. Members of the Old Orders are
tersWhatIsWrongwithOurBaby?,com-
not eligible for Medicare or Medicaid
piled and published by John and Verna
benefitsbecauseof anexemptionfrom
Martin,parentsoftwoMSUDchildren,
Social Security taxes. When young
isaninterestingandsometimessobering
adults join the Old Order Amish or
look at modern health care from a
Mennonitechurches, theysignanIRS
parent’sperspective[MartinandMartin,
Form 4029, which indicates that they
1995].TheoldestsurvivingMennonite
are‘‘amemberofareligiousbodythatis
patient withMSUD wasbornin 1967,
conscientiouslyopposedtosocialsecur-
butmanyundiagnosedor untreatedin-
ity benefits but that makes reasonable
fantsdiedbeforeshewasborn.Shewasin
provisionfor itsowndependentmem-
ahospitalinPhiladelphiafor6months,
bers’’[Hostetler,1993].Theexemption
did not regain her birth weight for
fromthetaxalsomeansthatthosewho
4months,andtodayhasseveredisability
signIRSForm4029agreenottoaccept
and retardation. Her sister, in whom
money from state or federal programs
3. MSUDwasrecognizedby3daysofage,
0 that are paid for by Social Security
þ þ þ þ þ 20 became severely intoxicated, remained funds. This cultural practice is one of
ger, hospitalized for many weeks, and also many issues community members face
er hasprofoundretardation.
b whenobtainingcarefortheirchildren.
n
þ þ þ uffe
P
n FINANCIAL DIFFICULTIES CHALLENGES IN
o
Osteogenesisimperfecta,AmishvariantRettsyndrome Retinitispigmentosa,areflexia,sensoryataxiaWerdnig-Hoffmandisease, infantileFamilialmanic-depressiveillness Geneandmutationidentificati FIMBMMmaHNneOoaeSdEtnwnwURTDanehegDRoveeIoP.ennCmsArLpi,tAeOieDAtnaaLvts1IlIceiN9TohzSrf6afuiIlEt6tndPOithoTrdhEeenNieTnnOnsageAeItnwiPNodmLfne2LoGera2rEestSe1rsbyse9heios8meoar8arnrp,srt,creowhnvtei3hetidhnd6e. TMTEansMcegeoavHHreSrAreemlUmirbEENeaerDarlSanlAMolEtdgdtGihEriaedDeoegEdDidwrndeIwMom,SItuhCisnOsEaiiesenAaNRxnhaaLpdenTfmDetadecldaEtOrtnheeiRmvyydFtelhcSplyocheraopiflsrvmdeonersmede,enwntamab,wlcloauoyinrtwtehne-t
a
biochemical causes of mental retarda- period.Ofthe36childrenwithMSUD
12 AMERICANJOURNALOFMEDICALGENETICS(SEMIN.MED.GENET.) ARTICLE
gramdidnotsubstantiallyimprovemat- 5 days with a hospital cost of $1,000–
Earlier diagnosis and tersforthesepatients.UntiltheGuthrie 2,000 per patient per day. Over a 12-
method was replaced by the tandem year period, developmental outcomes
improved management did,
mass spectrometry program in 1993, have been good [Morton et al., 2002].
in many cases, allow normal
false positive rates were unacceptably We currently follow more than 70
growth and development, high [Morton et al., 2002b]. The state patients with MSUD, most of whom
programmadenoprovisionstotestand are of Mennonite descent. Between
yet several otherwise healthy
provide immediate results for high-risk 1988 and 2002 we had 137 admissions
children with MSUD died infants. The three Mennonite infants to our hospital for acute MSUD in-
who were found by the state program toxication; however, the average an-
unexpectedly from acute
were 5 and 6 days old and already ill. nual rate of hospitalization for our
cerebral edema after More important, the state follow-up MSUD patients is less than 1 day per
the newborn period. program made no provisions to pay for patient-year of follow-up. Between
the care of ill neonates, had no plans 1988 and 2002, there were, however,
for the assessment and care of acutely no deaths from cerebral edema. The
bornbetween1966and1988,14(36%) ill older children, did not address the current total annual formula cost for
diedofcerebraledemabeforetheageof problemofcerebraledema,anddidnot ourMSUDpatientsisabout$115,000.
10 years. The typical course of the support care for patients over the age Again,mostMennonitefamiliesdonot
childrenwasthattheybecameillwitha of 21 years. The state program did accept formula or reimbursement for
common infection, had poor appetite, offertopayforseveralaminoacidlevels costs from the Pennsylvania MSUD
vomiting, and irritability, which pro- per year and offered formula to those follow-upprogram.Theclinicpayshalf
gressedtolethargy,andthentocoma.By who qualified for, and would accept, of these costs for families who have
the time arrangements were made to Medicaid, but the program required limited resources, and the families pay
travel from Lancaster to the regional that Mennonite families obtain these the balance. The charge for an out-
hospital, the biochemical intoxication services at the hospitals in distant re- patient visit is $35, and medical care
wassevere.Emergencyeffortstoreverse gionalcenters. and laboratory testing are provided
the intoxication by intravenous fluids, In 1990, an amino acid analyzer at the clinic regardless of a family’s
glucose, and dialysis failed, the cerebral was given to the Clinic for Special ability to pay. In summary, a com-
edemaworsened,andwithin24hrafter ChildrenbytwoMennonitechurches. prehensive health care system was
entering the hospital, the child died of To date, the clinic has performed designed to provide sophisticated
brain stem herniation. Physicians and 16,402 amino acid analyses on this medical care of patients with MSUD
parents knew that common infectious instrument. Because of our nonprofit withintheircommunity.Bycombining
illnessesprovokedseriousmetabolicin- status and community support, we community support and other dona-
toxication, but little was known about were able to reduce the patient test tionswithknowledgeableandsophisti-
how to control the metabolic response charge from $450 to $50. We also cated laboratory and clinical care, the
to such illnesses in the outpatient set- decreased the analysis and reporting morbidity, mortality, and costs have
ting. Local services for children were timefor plasmabranched-chainamino beenreduced.
limited. Specialists and equipment that acids to 20 min, and we routinely
wereneededtostudytheearlystagesof quantify plasma amino acids during an
CARE FOR PATIENTS
cerebraledemawereinresearchlabora- outpatient clinic visit. Between 1989
WITH DISORDERS
toriesfarfromthepatients.Theavailable and 2003, we managed 42 neonates
OTHERTHAN MSUD
biochemicaltestingwasofnoutilityfor with MSUD. Twenty-one of these
the rapid treatment necessary to avert neonates were from high-risk couples We believe that the cost of operat-
cerebral edema because results took as recognizedbyfamilyhistoriesorcarrier ing the Clinic for Special Children
long as 2 weeks. Routine outpatient tests, and the infants were tested for could be fully justified if we cared for
visitstometabolicclinicsinPhiladelphia MSUD and diagnosed before 24 hr of no other patients than Mennonite
could only be made on one afternoon age.Withtimelydiagnosis,theneonates children with MSUD. However, the
each week, and outpatient services to were never ill and could be managed medical and economic impacts of care
assessacutelyillchildrenwerenotavail- without hospitalization. The diagnosis for patients with GA1, MCADD,
able.Instead,illchildrenwerereferredto of MSUD was made in 20 additional Crigler-Najjar disease, the bile salt
emergencyrooms,andthemedicalstaff neonates diagnosed because of clinical disorders,andmanyotherdisordersthat
of the ER usually knew less about the illnesses; 3 of these infants were found affect Amish and Mennonite children
management of MSUD than did the by the Pennsylvania screening pro- provideequallycompellingjustification
child’s parents. Newborn screening for gram.These20illinfantsweremanaged for the clinic. More than 95% of the
MSUD was started by Pennsylvania in at Lancaster General Hospital by the disordersweseecauseclinicalproblems
1988, but the state-administered pro- clinic staff and had a typical stayof 3– during infancy. Ten of the syndromes
ARTICLE AMERICANJOURNALOFMEDICALGENETICS(SEMIN.MED.GENET.) 13
wide studies, including the cerebral foundtohaveMCADDattheclinicwas
More than 95% of the arteriovenous malformation syndrome, 14 years old and had been hospitaliz-
disorders we see cause clinical manic depressive illness, several conge- edseveraltimesbecauseofvomitingand
nitaldeafnesssyndromes,andacommon ketotic hypoglycemia. Her sibling died
problems during infancy.
seizure/mentalretardationsyndrome. atage6monthswithhypoglycemiaanda
fattyliver,whichwasdiagnosedasReye
syndromein1976.
THE IMPORTANCE OF
can be recognized by history and Here and elsewhere, some genetic
PRESYMPTOMATIC CARE
physical examination, including the disorders have been misdiagnosed as
commondisorders,Amishlethalmicro- In our clinic, we have emphasized the child abuse. Approximately 10% of
cephaly[Kelleyetal.,2002;Straussetal., importance of diagnosis of asympto- patientswithGA1whomwehaveseen
2002],Swareysyndrome[Mortonetal., maticinfants.Forexample,thediagnosis wereoriginallythoughttobevictimsof
unpublished results], a variant of cere- of GA1 after degeneration of the basal child abuse. Infants with GA1 may
bellarataxia[Mortonetal.,unpublished gangliaallowsnoopportunityforeffec- presentwithsubduralhemorrhagesafter
results],andanewlydescribedsyndrome tive treatment [Morton et al., 1991; minorheadtrauma,because75%ofthe
with infantile retinitis pigmentosa and StraussandMorton,2003a;Straussetal., infants have open subdural and subar-
sensoryataxia[Higginsetal.,1999].Five 2003b].Theprospectivemanagementof achnoidspacesthatarecrossedbybridg-
disorders are primarily diagnosed by GA1 prevents basal ganglial degenera- ing veins [Strauss and Morton, 2003a].
amino acid analysis,and eightdisorders tioninatleast75%ofcases.Theclinical These intracranial hemorrhages are
by organic acid analysis with gas chro- importance of recognizing asympto- usually large, and retinal hemorrhages
matography/mass spectrometry (GC/ matic infantswithMCADD,propionic have developed spontaneously in asso-
MS). GenomicDNA mutationanalysis acidemia,Crigler-Najjardisease,adrenal ciation with large intracranial hemor-
isperformedintheclinic[Puffenberger insufficiencies, Bartter disease, the bile rhages [Hymel et al., 2002]. In the
andMorton,2002;Puffenberger,2003] salttransportdisorders,andgalactosemia AmishpopulationofLancasterCounty,
andisnowusedtodiagnose19disorders, is readily apparent to a pediatrician we follow 28 children with three dif-
including Byler disease and two other who has cared for infants with these ferent hepatic bile salt transport disor-
disordersthatdisruptbilesalttransport, disorders who presented undiagnosed ders. Nine of these infants (30%)
Crigler-Najjar disease, fragile-X syn- andseverelyill. presented before 6 months of age with
drome,glycogenstoragediseasetypeVI Wehavealsofoundithelpfultobe bruising and bleeding secondary to
[Changetal.,1998],Amishosteogenesis able to immediately diagnose lethal vitamin K deficiency. One such infant
imperfecta, infantile spinal muscular disorders in neonates. GM1 gangliosi- presentedinacomawithafullfontanel,
atrophy, and methylenetetrahydrofolate dosiscanbediagnosedbyphysicalexam retinal hemorrhages, and bruising on
reductase deficiency [Puffenberger and and a single inexpensive test of urine bony prominences. Shaken baby syn-
Morton,2002].Twocommonlethaldis- for increased urine oligosaccharide dromewasthesuspecteddiagnosis.The
orders,troponinT1myopathy[Johnston excretion.Infantilespinalmuscularatro- infant was subsequently found to have
etal.,2000]andinfantilespinalmuscular phyandtroponinT1deficiencyareboth a vitamin K-responsive coagulopathy,
atrophy,canbedifficulttodiagnoseina routinely diagnosed in neonates by high serum bile salts, a deep, intracer-
newborn byexamination, and we now molecular methods at a charge of less ebralhemorrhage,andunilateralretinal
routinely confirm these diagnoses by than $50 [Puffenberger and Morton, hemorrhages, which were atypical of
mutation analyses. Neonatal metabolic 2002]. Because of easy access to the shaken baby syndrome. This infant and
screenings done by Neo Gen Inc. clinic,prolongedhospitalizationsinvol- her sibling are now known to be
identifyusingtandemmassspectrometry ving multiple invasive and expensive homozygotesforamutationinthetight
routinelyidentify14ofthedisordersthat diagnostic tests for lethal disorders can junction protein 2 gene [Carlton et al.,
we see. The preliminary biochemical usuallybeavoided. 2003]. Fractures caused by relatively
diagnoses for most of these disorders is Intheprimarycaresetting,undiag- mild types of osteogenesis imperfecta
confirmed in our laboratory on the nosedgeneticsyndromespresentdiffer- foundinthePlainpopulationshavealso
original specimen through polymerase ently than in genetic clinics at referral beenmistakenforchildabuse.
chain reaction (PCR)-based mutation centers.Mostoften,theinfantswhoare
detection. The molecular basis of 17 seen at the clinic are irritable, feed
THE UTILITYOF
disordersseenattheclinicremainstobe poorly,gainweightslowly,andinother
A DETAILED
identified. Seven of these disorders lesswelldefinedwaysseemtotheparents
UNDERSTANDING
shouldyieldtocandidategenesequenc- to be ‘‘just not right.’’ Many teenage
OF THE NATURAL
ing, including GM1 gangliosidosis, patients and adults in these populations
HISTORYOF DISEASE
Bartter disease, and polycystic kidney withunderlyinggeneticsyndromeshad
disease, whereas 10 syndromes without notbeenevaluatedbymoderndiagnos- We have had a unique opportunity to
candidate genes will require genome- tic methods. The first Mennonite girl observe the natural history of these
14 AMERICANJOURNALOFMEDICALGENETICS(SEMIN.MED.GENET.) ARTICLE
disorders in many patients. The Men- deficiencies. Our impression is that measurementsofplasmaaminoacidsand
nonite variant of MSUD arises from a prolonged deficiencies of valine in the changestoadifferenttreatmentregimen
stopcodoninexon1oftheBCKDHA brainduringthecriticalperiodofrapid to prevent prolonged or progressive
gene. Thus far, all Mennonite patients braingrowthbetweenbirthand2years metabolic intoxication. The ultimate
havebeenhomozygousforthismutation of age may be a major factor in mental impactoftheseillnessesonclinicalout-
and all have the classical form of the retardationseeninchildrenwithpoorly come is influenced by the rapid avail-
disorder. In spite of the mutational treatedMSUD[Mortonetal.,2002b]. ability of outpatient and inpatient
homogeneity, the phenotype ranges ThemainstayoftherapyforMSUD services, including amino acid analysis,
from patients who are profoundly dis- has been the dietary restriction of the MSUDhyperalimentationsolution,and
abled to those who are apparently branched-chain amino acids. Unfortu- medical care by physicians and nurses
normal.Pooroutcomesinpatientswith nately, in many follow-up programs, whohaveexperiencewiththemanage-
MSUD can usually be understood in leucinelevelsaremeasuredinfrequently mentofthemetaboliccrisisandcerebral
terms of one or more of the following and isoleucine, valine, and the other edema.
problems: delays in neonatal diagnosis essentialaminoacidsarenotmonitored
and treatment, chronic essential amino atall.Itisnotpossibletounderstandthe
acid deficiencies, ineffective manage- relationship of day-to-day metabolic The ultimate impact of these
ment of metabolic intoxication during controlandneurologicaloutcomewhen
illnesses on clinical outcome
infectious illnesses, and acute vascular only a few plasma leucine levels are
braininjuriescausedbycerebraledema. measuredperyear.Intermittentchanges is influenced by the rapid
Neonates with MSUD who are diag- intolerancerelatedtonormalvariation availabilityof outpatient
nosedbefore24–36hrofagearenotill, ingrowthvelocityorillnesseswillnotbe
and inpatient services,
and progressive metabolic intoxication appreciated. Deficiencies of branched-
can be prevented by rational manage- chain amino acids and the unbalanced including amino acid analysis,
ment [Morton et al., 2002b]. Plasma transport of the other neutral amino
MSUD hyperalimentation
amino acid quantification allows diag- acids that compete with leucine for
nosisofthedisorderasearlyas12hrof entry into the brain cannot be assessed solution, and medical care by
ageifhigh-performanceliquidchroma- by isolated measurements of leucine.
physicians and nurses who
tography(HPLC)ortandemmassspec- The effects of dietary therapyon intel-
have experience with the
trometryisused.Itisimportanttonote lectualoutcomecanonlybeunderstood
that the Guthrie bacterial inhibition by reference to the cumulative effects management of the metabolic
assay is not sufficiently sensitive to be of amino acid metabolism throughout
crisis and cerebral edema.
used for specimens collected before the critical period of brain growth
24hrofage[Mortonetal.,2002b].All and development. In recent years, we
infants with classical MSUD identified have monitored blood amino acid
by newborn screening programs will levels in rapidly growing infants twice
MEDICAL CARE AND THE
be very ill if screening results are not weekly and gained an appreciation of
OUTCOME OF OTHER
available before 4 days of age. Infants how quickly amino acid concentrat-
GENETIC DISORDERS
identifiedandtreatedbetween4and10 ionschange,especiallyduringotherwise
days of age can have goodneurological minorinfectiousillnesses. Eleven of the disorders that affect the
outcomes, but the cost of initial treat- Over a 13-year period, we have Amish and Mennonites are lethal or
ment is higher than those diagnosed admitted patients with MSUD to the invariablycausefulldisability.Although
within 24 hr. Neonatal screening pro- hospital for management of metabolic these 11 disorders are lethal, affected
gramsforMSUDwhereinspecimensare crisis137times.Morethan120ofthese children may live months or years and
not collected until 72 hr of age and admissions were necessary because of require many human and medical ser-
resultsarenotreportedbefore14daysof catabolic intoxication caused by infec- vices. The clinic routinely provides
age can expect high initial costs of tious illnesses such as gastroenteritis, medical care for children who have
treatmentandhighmorbidityandmor- otitis media, streptococcal pharyngitis, lethal diseases. Most of these children
tality. After MSUD is diagnosed, the sinusitis, and pulmonary infections. arecaredfor,anddie,athome.Muchof
prognosis for the patients depends on Appendicitis, cholecystitis, torsion and the community support for the clinic
several variables,includingthetimere- infarctionoftheovary,andfracturesalso comes from families who need and
quired to lower the plasma and tissue cause metabolic crises. In addition, we appreciatethiscare.Theother51meta-
leucine levels to normal, prevention of have 100–200 MSUD outpatient visits bolic disorders and syndromes present
the vascular compression and ischemic per year to manage infectious illnesses with a range of clinical problems that
injuries caused by critical brain edema, andotherstressors.Theseillnessescause require timely diagnosis and ongoing
and prevention of prolonged or severe significantmetabolicchangesinpatients medical care. Our daily practice in-
brain and systemic essential amino acid with MSUD and require one or more cludes management of episodic crises