STATUS OF THE HETEROZYGOTE FEMALE* BY Alex E. Krill, MD

74 Pages·2005·11.12 MB·English

X-CHROMOSOMAL-LINKED DISEASES AFFECTING
THE EYE: STATUS OF THE HETEROZYGOTE
FEMALE*
BYAlex E. Krill, M.D.
ACCORDING TO CLASSICAL GENETIC THEORY females carrying a gene for
a recessive trait or disease on only one x-chromosome (heterozygote
for the gene) should show no manifestations of the defect. The usual
explanation is that the defective gene of one x-chromosome is recessive
to a normal gene at the same locus on the other x-chromosome (an
allele). However, because of several examples of structural and func-
tional abnormalities in females supposedly heterozygote for recessive
traits, this view has been questioned for several years now. In fact, an
entirely new theory to explain x-linked inheritance was even proposed
in 1961.1
The purpose of this report is to review proved or suspected x-linked
diseases in which the eye is affected; to describe any abnormalities
that have been found in heterozygote female carriers; and to sum-
marize the various theories that have been proposed to explain the
status of the female with particular emphasis on the inactivation
hypothesis, the most recent theory.
THE SEX CHROMOSOMES
Until as recently as 1956 it was believed that the human cell had 48
chromosomes. However, in that year, Tjio and Levan2 found that
every human cell has 46 chromosomes with the exception of the sperm
and the ova, which have 23 chromosomes. Forty-four of the 46 chro-
mosomes are called autosomes and can be grouped into 22 pairs of
identical partners. Each pair, though, is different in genetic content
*From the Eye Research Laboratories, The University of Chicago, Chicago,
Illinois.
This study was supported in part by Grants EY-00523, EY-00277, NB-03542, and
FR-55fromtheNationalInstitutes ofHealth, PublicHealthService.
TR. AM. OPXim. SOC.,vol. 67, 1969
536 Alex E. Krill
FIGURE 1
Sex chromosomes of male showing an x-chromosome
and a much smaller Y-chromosome. Segment ab of /
the x-chromosome carries all of the known x-linked
genes. Segments bc on the x- and Y-chromosomes b b
are similar in morphological appearance and are said
to be homologous but no genes have been traced to I';
this area. On the other hand, segments ab of the
x-chromosome and cd of the Y-chromosome are C
entirely different in size and morphological appear- _
ance. It is only in segment bc that interchange and _ _d
crossing over of genetic material can occur. X Y
and frequently in appearance from other pairs. All pairs except one
are the same in males and females. The pair of chromosomes that is
not identical in the two sexes was named the sex chromosomes by
Wilson3 in 1909. This unique pair consists of two similar chromosomes
in women called x-chromosomes and two dissimilar chromosomes in
males (Figure 1). One male sex chromosome resembles the two fe-
male x-chromosomes and is therefore also called an x-chromosome
and the second is unique and is called the Y-chromosome. The Y-
chromosome is very strongly male-determining since the presence of
testis and some secondary sex characteristics are dependent on the
presence of this chromosome.4'5
Chromosomes are made up of units called genes which are the
basic units of heredity. Genes are too small to be seen by modern
means of examination. However, chromosomes are visible in actively
dividing cells, particularly during metaphase when they are ready to
separate. Colchicine stops mitosis at this stage and is therefore added,
after a suitable incubation period, to cellular material obtained usually
from either peripheral blood, bone marrow, or skin. These cells are
then exposed to a hypotonic solution, which causes them to swell and
spread out so that they are more readily analysable; then they are
fixed and stained.
In general, chromosome pairs are classified according to their length
and numbered in order of decreasing size (Figure 2). The longest
chromosome is about 7 to 8 ,u in length, and the shortest is about 1.5 ,u.
Each chromosome consists of two long thin parallel strands called
chromatids, held together at one spot, called the centromere (kineto-
chore). In addition to the length of the chromosome, the position of
the centromere and sometimes the presence of satellites (small hetero-
-+ -w 1 s - s s
X-Chromosonwl-LinkedDiseases
537
:-':.;.::.':..-::.::%-.'..X-.'::-X.:-:.:;'.::I:.:2.:::..-.X:...:..:....::.:-....:.:..'::.:.-.::'..:.-::::.:,.:::::.-..:.-::.::...:....%::.:::".::..:'::::...::4:;.:.:'........:::...:.:"..::::..,:.:..:,:.:..,::..%7:..:-......::...::.....-:....,..'.:.:..-.:..:.-.....:7.-::...:...:,.::.:..X..'A.-.::.::::.:.:..::N-:-.:.:.:::.:.:'.:-:.:..;::%:-.:::N1.::-.!:v%.:::;:.:':I.:::-.y..::1:::...::..wi%:.:::.N-.:.:..':..%..i::-.:..::...':':.....'!',.::-H.%.:.-.'..?.:.::.i.i:....::.:.f.:.x:.:.:.I:::f';.'i..:::.:.::::'::......i.:::-N:.%..::....i:.%:.%...%......:::i.:.:%.iN....::.:.-....:-:::...-.-:.":%::.....".:::N.i.:.-:.:..i:!;.'..::....:.:.:::...::...;:::-...!.::.::.::E:...:::.::.'.::.;.::.::-.,.....X.H..::.:.....:::..:;::!...:::.:..:W::,:.:-.::::....:...::.:.:.:.:.::.::9':..--.;:-"%:..:.:N:.:4.-::..::..:,:.:i::.::.i.....::ix::::.:.NN.%":..:.::'%....:.:C.."%.1.:::..:.:..:,:.-::..':i::1.,::.::..:..:..:-..::..:::....:...::-.':...:::::M-.-:%.."%:::'.:..:..l.-:....:N:::..":::....'."::.:::::".N.....:.-:N,i::X.;.:..:...:.:.::X::N!-%:.l-:...:.....::.-:i.::,.=.:..:.i%.:::::.,:;:2':.X..:::::.....:.::.:.:.:.:.::.::..:s::.:.::.E::::.!:.:::::..:::::..:::-.'::i!:.::%::4:.::.::.4.:.."-N.%::'...:..:::..-..::'.:.-::":..:....%::;.:.:,":...:N:::::'.::":i::.;".fX..::.:.::":.:::N..:..:..::..::M'.:::::N;:'.'::.::.:.5M.:::iX..i-N-:::.:%::.:..:..:II:...:::::N:.'.:-:...4.':..:-...A-::':::::-..:;1:::..N:'..!.:"%-':-.:::.:-..:.:..X:M::...,.%..z::'..4X:.I:..:..::::..:..'::N:::.X!..::.....:-:':.,:....:;..M.::!I:.::.:'-:':::.:1.:M:.:.1'::1..::".:.:::.,X:.::......:.iN..::i::'...::.N..,:.:.:.'.::1..3...!:..::::...:..-:::...!.4,:X::.-.:...:N.:.::.:::.::N..'.:..:-::,...:1.::.:..A:;!..:..CI':"::::-:..::...:.%'..:'..::.:.-...1..N:::....%:;.-.:.:..::.:NX:..:.::.:.,:...::X:':...:.::...XI%....::N:-.4X%X:.N::.N::.NN.::..::1.:-.:'-.f..:4..:::s.....::..%-::-1...:1.e-N:.-::';:.....:-::-:l.-.:..N:x...1.--..:::'..:..:::_N'.-:!-:.:..-..:::::.:'.:-:::.::::.'..iX.%.:i.:.:-:::...,.:%:::::..-:::..::!::::.-.:.:::.::iN.:-:.4..:':I!:...'..::.-:.::,..:..2..:4;.'W:::.i.:v.-...:...::.:%..:.::.:.:..:..-..:::-.:.:...X%...:N:.:::.N::::.-.:%..-....:::.!..'.!.::::-:,:..;.-..,.,..-:O4.-.:7':.I..:::.%:-:::..i.:i.-:..:.:.:.:.":4::.:9..:."..:..-:::...-.:..--..:?:..::..:.;:::....::i.:.:.'..!:'.%..-:.:..::.X::.X...%.::.f-..:.4...::-.4:..:N%-:......:.:..':::N..N......I..:%."4.:..2:,::.V?...:.:.%:...:.::X'::X":%:....-:....7:...%:.:.:-::.,..:...::::.:':.:,:'.:::,..:....:::.:X..::"..::.:.:-.X:::-::::...:.-%::'-.:::-h:::.-:..":..::::...-1.:,:i...:.:,:-N:.X:::::..::.-.,.:.-.::.::.::::.:%::.:7:::,..::-.::,..Z..::.:::'::...-:::.:i::.'-.::.:'!.:::.::.:.N:X:::MIX4:-,,;::....:.:."..:!..:.4::..-:i.3::m.:::,:i%-:N.::.N:.:4::-.x..::.::NN:%:::::......N:..--:N::L:!:..:::....:...1-::-:`...:.xN...-:.:..:..:.1:-:.:.;::..::'...-.4:.:.:-.'.....V.iX:::..X.--:::::.:..:::N:N:4...:-:..%::':::::,.:...:.:::!:.-N:::..::::':.:..:.:...:-.::.:.:.-.:.:.:..:.:..:!W:....:::.:..-.:.:..2...%::..1::'-4-:::IN::::'.-..:4...::::;'.:...l:,.:%--.:ii:.:...:.::::-:-.%..:".XN..:.::::,-:.."-:.::.!'"..:z.%..."4..:.::::-.-.:...-..::.:..''....::..:4:.-::":..X.,.:X...:....::-:...:.:.:::4...:::..i::.X:::.::::..:..%':...::...N::.%.::!N..:X.'..:.':-%:".::..:'M'-..''::.::%N'..,.::.::-.!.-X.:.::'-1.'.:N.:.':i.-;.4..".::4:.:.:.':y..:.':4,:::.-.':N:::.:.:...:.:......s::.:::.1.:..:.,::.".':!C..-:.:.:.::':.::1.:'::X:R::X.:..::N'..!.::.:....::..4:R.:%.:.:M..:.4....::.-::.:..:.s..:X'.::.::.:::N...:.::.-:-....:.::..]....:.:-::%,.-4::g1:::..:.';:..-.:::M....::-..:::::':..:":.--...:.:::.:N-::.",A5.::..:..::..:'.:.::::...":::..::..::,..:..::......:..::.'.:.:.:.:.:..::".::::I..:1..:":V.:::"..:...:.:....:..1,:%:::...:.,.N:i4:.:....:1.....:z..:.::::N%:..:::-:::::::....:.:6:.1.:.:::.'i..:-.:.;.N:..:.-::;-.X..:....N."..:.::.:X-:%."%:.:.:.:::.:::.........-.:.::"..:....:I:.'::.-....:::X.:-.:.=--::N,:::.:,':::.:::-"X:4.:-..:.:.:l.%'.'::.:...:.:5..::.::.z:.:'.X.::::...:;-'..::'....:.::..::::4%i.:a':...:4..........::4::-..."::.!..:.:-:.:.:.-:i...:..:..........XX-..:'%:.:..:::..-..:-::.:.-X4::.:.:::.:..:-::.:!::.::.::.-::::_:.:.'::.:I...:N......:':C:.,:%.:...:.:X::!:':1:.:.N:4:::.-.:.:'-:.:..".L-::-":.M::..'..:..:::':.:'-X..:.:m:'".:.:.:".:.:::.....:9.,.':.:.:..%-:.--.:..-.::-2.-::i...-1.:.'.:-'-"::.:.-:..:.t'4..,.--.7:.':.-X%::::....:'..::4:::.:N%.:-N!X.:..%:.::::.:.:::-::.-::::..::%::::.X!::.%:_..:.::.::..-..':.''.:4:.::::::-N..:..N.%:::X..::4X!:!:::.-.:.:.:;....:.:.:'.:-:.:.:X..:t:-::.-.:-::::::..::..'::.:::.....;.:;.M.:.%N:.:..1-Z..::!.:':.!:-.z%%::.::.::-::::-..X..::.:..-:X::".;:.;.-.N::::.M..:::::.,Q..::.:.:.1'::..::.::.-:::!;::":N:::..NIN.:_y..:.:...:':..:.N.::'.::N..:.:...::-::%.::Y::X::..::.::4::::;:.I:::4.:..!-:.:..::--.::N%:..:1:.:.:.:,.:..N::::::.-.::.zM:.:::':;.::-::.......:..::-:.:!..::::-2::..::.!..:.;N.14.--::..:.:.:...:*::::::.:::.:.-:...:y.i:X:::::.-.:.1"::-::N;::::::::.-:.I:,..:r.X......:.::...:;:%...%::-.:::.::.-.:'..::.'.:-":-...::.:.:.1:.x::::.:%....:%::...:,:.%.:N-X.:X,.::....:h..:::...::.:.%:.:.%:::%.::.'-:..:;':.:....N.:..!...:.:::N:.:..::X'-..:.:..:::.:..:-::..:..%.":.:::-.::'...-.::..;:.:.::::..::...:::.-".;-.:..::'::X.::::N.:..:%X:-..--X%?:".-.:-:-:4::.:....-..::.N!.':..M.::.::-::.X:.:-:i.:,....::::...!:::....::,.....%-::.-:I-;:x.:-..N'N:z.:.j1..:.:..-.:.X::.!:::..N.:.:-.N::.:...:j.;.-..::::...;:-...,.--....:.-:.:.-..:."X.:...:%::-.:..,::::N::4.:!.'.;:..::.:......%-I..:::N..'.'.i-::'.-.:.;.:...:..:.:-.:..!.!:.X',::.-..:;,-%..-.:.,..:".:Nt.::.-.;:.:.:1:%::..:..N,:.:-:................1.:...:!.,::::-..-:::.:-:.:.:.i:i:..i.'..:-'::...:::s';:..-.-."..::.:.:::.::.-::.:':-::-.::....:....::iNx%:1...!.::::::.L:'....l...:::.:.:.::':...-:-.::%,:.:.:.;'::::4:X::.::::...X......i.:.:..-.::.:..'.".N.%:.:::::.,.-:..:.:::..'N::-::.i.!....:::.:::..::::%..;:N.:..:':.,h...'..:.:..:.-'.m..::.m:.-::::'N:::.':..X..-...:-.-..'..%::.::--:.-.".:..!..::.::;:C!:.N-....:.:...:..:.-...--:i.':..::-.::::.:!:.::.:..-:.,:.:::.:sI.:..'4..:....::.:::...:i::..::::%::.::..:..:.:.-.:.:..:-"-....:...Z.N.....',.--'.."...:.:,:::.;-:1:N..::.::-..h::.,::..:.:,.:......4.:.:"-N..N.-.X-:-:x-"..";:.-.::N::::..:-:.:.....:..:.l.:1.::.:.:::.:':::I.:.:..::-:X...::::.s.%:-;.N.:...::.:.:::.:::::..-::':1.::.::."::..'::...4:%:,.:..-::.x.:..'..%.".:N.-::,'::.%::-.:..:'::::-..:...:.::...:,.:.:-:...:.:...:.:..:..:-:::."z'::.:.::.::'.:.%:::.':::.::..::'.:::..::Q..:...-:"..',:.:N.:..'..:..:..:%':::..::.:.:.::.::"-.-:-:X.-...4::...:..::..N::.-:.--:-:.M%:.:XX.....:::..:V:.-`.%..:...:..-::'.:::X:::!.:.-::.-.:.:::.::...:.:.%...:.:.:.::.:.:..!:.:'N-..X-.::i..:.:.-:.,:.:..:::..::::::.X:D.N%::..::!:%:.::-.:.:::..:NXN%..i:.':':.,:..::.N.':-:::....-.::.::::.:::1..-.::-:.-::..:.-i:-O.X."-I:-.-.:1...::X::'::IN.:.'..:...::::::....:.:i.x::..:.%:...::X.:N.:.X."::::X::.:.::.-..:.::..:.:i.::.1.!.:....:::::.-N::.M.::..N.:I:-:.-.:..:.:..:M-:':%.:::..:.:.:.:...:::::!.:..:'..:::-.:...::.'-..WN::::..;x.:.:..:::.::N.:.:.::':.:...-'::"::.1:::X:..-.:%::-....::.'........-.'::...:::,:-:..":.:.....":,.::::..Q:4.:::.:w!.-:.::.N::N:::.I":-.l-:-:.....:...'%.:.:..:%::..........X.:.::::.-i:-...-!::-::,:.-:..::-..:-::......:..:::.!-!:N:.-...iN...::..Nk.......:::::%..%.-..-"::M%.-.-.-....:.%X.,.:-.7.:....:.:::::.Q-....:%:.:....:.:.:X:..N::.:...:.:.::::.:X.:!:.::...;--.::.-.::i.-..:N.:.:::::.:..':x..":..:...--:.-.'.:i:.I.:%::::.-.:..:.::.:..':V'..:-::-.:....:..:...::.:i........,::......::::...:-...!....:i:."t..-...4N:."...-..'.:.:...i.:...O..:.-.:...:..::"-.......:::.....:::::':.-.:.:''.:::.:...:.:..--';'%:::.:%:i.N::...:::a.:..:"...:..-.:.::..i::.::..--:'":::......-:.::-...:-..:-......:"......:.:...-,:..:.:..:-f...-:i.:::.......:::-A.X-.:..i-%I:`;.-.:.:...:..:N::.:-i:!,%:.....:.-....::::-.::...::...:.::.:...7...:..-..:1:..':..:,.-.....::Wl::.%-.,.1:.:'..:::.:,...::".:X.......!.':'..:.:...:.:.."i:.,...-...:::.:.:..-.'......:....1::.-...:-..`::.:::...:..i:N..::.--.'...:..:..-1:.:%:-'::.":--:...:1......m:'''....''-:::..:w.:---'::1:,:?::..%::::..::i:..:--.-,N::..:.:::...::...:.-.:::::.":.:::4-.-:.,:...:%:::':.:."::.....i:.:.:.:.:.:-:.::".::14::.:...:;:::.:::.`:.:.s.:.:::::.::-....!:..:%-:..:N.-'.:.:-:."...:!:::'-:::':.:.::.N."..:N..:.:%::..:%::.:N.:;..:-:.:-..-::::::..::.:i..:::..:.:-.4.::-.::.:..:X:::.:.:...:..I.::.:-:-.::1..:.':.-::.:N.7..''.::::.:"..4:::.::.!._..-'::::.:.:-..:.:::-:::..:..:...-.::.::..-::.:-:::.-O-.:::::,:X.:"i::.:..::..::N::.:..:.:...-::.:N:::.:::%.::..:.::I:'II.::.::!.ZN..::::.::2:.:::...:.:.%:.:.::-.::::.::::.:-:.'.'..:,.:.:..%.:...:N.:::.N-::::,.:%...:::.".::.:....f::.X4..::...:..:.:..':....:...::::.::..::.:.."..:...-..:.":...N...:..:,.%::.-:::.-..N.::-....:..:.:.....:'.:::!...::::.:.:i.,..:.:.::..::-.....:::-N.:..%..:.:4.:.::...:::%.%::.:.%:.::::':::..:-..N:,.::!.:....:%.:.:.:i:.:.:..-.-:.:.'.:...::-:.:..:.::.:..'...::i:::::.:..'-.:'...%..-::::..::.N%f.4!...::4..-.N:--.:..:::...::.:I..:.:::.:.:%'-.:'::.:'.::::N:-...1::.::";.%..::iIk'..--.:::.....N:':.::.'.::.,::...N%::..:.-:.:.:::...:-.'::-:.:..,:::.::::'-.-::.:.:.-.:.,..:.:.":..::...:.::.:.:-:::.::4.......NV-::':-".:..:f::......:.Xn..'.-.:.%-.::...':NN.:.::.:-.i."..:...-.X:.:.":-..:.A.-...:::...:..:.:...:::::-.-::.":.:.::'..:.X.:X-..-:.'-:1:':i.:..:.:-:4:.'.:-:::...::-:::..'.'::::...::::::.:%:...:...----:%:.:'...N:::::::.:6:..X:8.:.::-"..::.:N.-::..N:.:B:-::-::::.:.....::.-::..:.'::::.-:.:.-%.....::-..:...::.'::::::.-..:.::.!I.-:'-::.:.::..:-:..:I.X:::N.;..::'.::-:M:.:N'N...:...:.:.:.--%..:'N.::.::::.::M'.:......:..:::::.'.:-%..:.:':.-I..-::':-..::.:.:::--:..::::::-.:.:..,':.;:::..:::N:.-.:::.:.-F:42N.-..::'.:.:N.'4N'...::'.::.:::.%.-.::.:-.:.::i.:...:::%.:.::.,.:...-:..::..,.:.::..::..:::::.:.!.-.:-..N:..-f..'.:::::x.:.:.:..i:::!.::N:N:.:.:.:.:i:%.:.:.:.2.:..Y::.i.:..:N.:::..::.:i!..--."".:::!".:.-.:'.':...,,'...:i..:..iN:..:.::...:::.%::i:.`.:%.:%..:.:..'.%...:.:::.:..:'::.:%...:.::'::..:...':-..Ni..W:-N.-..:.::'I:--..j-:..::':.:.:%-'.::N.:...:.-.::.::.:...:.....::--:....::::.-...:.::X:.1-%:.:::,-::.:..-':--.'.:..:...:P::.::N:.'.-:::::..::.:...-.:::.:.:.:::.::-.:N:..,.,.::..:.......::%..%...N..:%.-N.:'NN;:....::...::....::......:.:.-...I.......N.......:...:%:..:...:..%.%:.....:...:.:..:....:....:.:...............N.:.::.N.:...-....
538 Alex E. Krilt
categorized into seven groups identified by the letters A through C
in order of decreasing length and position of chromatid (see caption
to Figure 2). Audioradiographic characteristics after labeling with
H3-thymidine may be utilized in the future as an aid in identifying
certain chromosomes.6
The two x-chromosomes of a female, although similar in length and
position of ceiitromere, show a number of differences. During the
prophase of cellular division, one of the two x-chromosomes is more
heavily condensed, takes a darker stain and is said to be hetero-
chromatic.7'8 This heterochromatic chromosome has a laterDNAreplica-
tion pattern.9 It is frequently seen in the resting phase (interphase)
of somatic cells as a small, very intensely staining body most com-
monly situated at the periphery of the nucleus, just inside the nuclear
membrane and called the "Barr sex-chromatin body" or the "Barr
body." This peculiar staining body, first identified by Barr and
Bertram'0 in cat nerve cells, has been identified in most mammalian
somatic cells. In humans it is usually searched for in buccal mucosa
smears and normally is seen in close to 40 per cent of such cells from
a female. The appearance is similar in most cells except in polymor-
phonuclear leukocytes where it appears as a darkly staining lobule
attached to the nucleus by a stalk and is called a drum stick.1' The
distinctive morphology of the Barr body in these cells is a reflection of
the peculiar shape of the nuclei of the polymorphonuclear leukocytes.
The two male sex chromosomes differ considerably in length, the
Y-chromosome being much shorter than the x-chromosome (Figure 1).
These chromosomes have homologous segments, which are similar in
morphological appearance on x- and Y-, and non-homologous seg-
ments, which are dissimilar on x- and Y-chromosomes. Obviously the
non-homologous segment of the x-chromosome is considerably larger.
It is only in the homologous sections of the x- and Y-chromosomes that
interchange and crossing over of genetic material can occur.
A trait determined by genes carried on any of the sex chromosomes
is called sex-linked. Traits determined by genes carried on the homo-
logous segment of the male x-chromosome are called partially sex-
linked. However, no trait or disease has been as yet traced to a gene
supposedly present on this portion of the x-chromosome. Traits deter-
mined by genes carried on the Y-chromosome are called holandric,
but only one trait, hairy ears, is thought to reflect a gene carried on
the Y-chromosome at the present time.'2 All other sex-linked traits
or diseases are thought to be due to genes on the non-homologous
segment ofthe x-chromosome.
X-Chromosomal-LinkedDiseases 539
A male with a defective gene on the x-chromosome is said to be
hemizygous for the gene. Since there is no normal gene to oppose the
defective gene, its resulting trait or disease, whether dominant or
recessive, will always be manifest. On the other hand, a female may
be heterozygous for a gene (present on one of the two x-chromo-
somes) or homozygous (the gene is present on both x-chromosomes).
Since most sex-linked traits or diseases are said to be recessive, two
defective genes are usually necessary in the female before the typical
condition is manifest. If only one defective gene is necessary, then the
condition is dominant. Obviously the terms dominant and recessive
aremeaningless in the male.
The distinctive feature of x-linked inheritance, both dominant and
recessive, is the absence of father to son transmission, since the male
x-chromosome passes only to daughters. All daughters of an affected
male will inherit the defective gene. One half of the sons of females
carrying the defective gene and one-fourth of the sons of all daughters
of carrier females will be affected. If the trait is recessive no daughters
of affected males should be affected although all will be carriers. If
the trait is dominant, all daughters of affected males will be affected
and 50 per cent of the daughters of an affected female willbe affected.
The proportion of affected sons of carriers and of carriers' daughters
will be the same as with an x-linked recessive condition. Occasionally
an x-linked dominanttrait is lethalinthe male so that the affected trait
is seen only in females. An excess of affected females in a pedigree
should suggest the possibility of x-linked dominant inheritance.
In summary, then, an x-linked trait or disease is manifest in the
female when: (1) the condition is dominant, or (2) the condition is
recessive but the female is carrying two defective genes, or (3) the
condition is recessive and she is carrying only one defective gene but
she has, similar to the male, only one x-chromosome (Turner's syn-
drome). As mentioned, though, there are many examples of females
with two x-chromosomes who are carrying only one defective gene
for a "recessive" condition but nevertheless show either partial mani-
festation or, very rarely, full manifestation of the condition. It is here
that our classical notions of "recessive" and "dominant" have required
modification.
MATERIALS
In some of the conditions to be described, x-linked inheritance has not
been conclusively proved by the absence of male to male transmission
but is based Qn faQtors such as the high frequency of the disease in
54( Alex E. Krilt
males, the minimal or absent findings in females, and the "oblique"
pattern of inheritance (unaffected females to affected males). As
previously indicated, x-linked dominant inheritance is suspected with
an excess of affected females or with only affected females. Some
conditions may not be unique and evidence is presented for this con-
clusion. A few conditions to be discussed do not have x-linked in-
heritance but are considered because this mode of inheritance was
ascribed in the past or is still ascribed in some sources at the present
time.
The abnormalities described in females in the various conditions
are derived from reports in the literature or from our own experience.
Some of the original abnormalities noted in our laboratory were
demonstrated by means of retinal functional testing. Our techniques
for color-vision testing, dark-adaptation evaluation, electroretinog-
raphy, and electro-oculography have been previously described.13-'8
X-LINKED DISEASES
INCOMPLETE TOTAL COLOR BLINDNESS (MONOCHROMATISM)
Blackwell and Blackwell'9'`0 described a form of incomplete total
color blindness which they called "blue mono-cone monochromatism"
because blue cones appeared to be only minimally involved. In con-
trast to typical total color blindness with autosomal recessive inheri-
tance, this condition has x-linked recessive inheritance.2' Visual acuity
is reduced as in typical monochromatism but to a lesser degree. These
patients have a mixed luminosity curve at high photopic intensities
and a scotopic type at low photopic intensities. They demonstrate
evidence of blue-cone function on certain psychophysical tests.20'22'23
Myopia is commonin affectedmales.
Female carriers with manifestations have been noted. In one
family,24 carriers showed delayed dark adaptation and a subnormal
a wave of the ERG. In another family,25a one female was a deuter-
anope and another, who was too young to completely evaluate, had
both photophobia and nystagmus.
In a family we studied (Figure 3), the mother of three affected
sons had a slow rod-cone break time of 20 minutes on dark adaptation
(normally this does not take longer than 12 minutes17) and a low
flicker fusion frequency on the ERG (Figure 4) of 35 cycles per second
(compared to a normal average of 70). This frequency, though, was
much higher than that obtained from two tested sons who both had
fusion frequenie5 of 4 cycles per sownd, In addition there were
'2~~~~~~~~~~~~~~~~~~~~~~~~'
~~~~~~~~~~
N J0
F4~~~~~~~~~~~~~~~~~~~~~4
0 Cd
N
cm~~~~~~~~~~~~~~~~~~~~~4
_ 4)
0~~~
o~~~~~~~~~~~~~~~~~o
o0~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~r~
- ~~~~~~~~~r wCkC.)U>,
- U)~~~~~~~~~~~.U
o ~ ~~~~~ ~~~~~~~~~~~~~~~~~~ * ow
e0 0~~~~~~~~~2~~~~~~~~~~~~IL~~L~~z~~~w~a~~~~~~~~~~~~~~40 z 0 z
z
_ e >m _ 4bts
C)
4)
0
-CI~~~~~~~~~~~~~~~~~~~~~C
LO~~~~~~~~~~~~~~~~~~~~~~~4
N~~~~
%44
~~~~~~~~~~~~~~~~~~~~~~~~~~44
cg
0
5.942 Alex E. Krill
TOTAL CONGENITAL COLORBLINDNESS
(SEX-LI NKED)
en 250-
I- x Female Carrier
J
0 A Involved Mole
° 200- i Normal Mean ± 2 S.D.
-,
0
w 150-
-
a- 100-
4
w
< 50
A
0D
A
x
0 i 2 3 4 5 7.510 I 203o04o5s o 0
FREQUENCY (CYCLES/SECOND)
FIGURE 4
B-wave amplitudes at each frequency from male iv, 7 and carrier female ii,
14 are plotted with normal data. Flicker fusion frequencies of four cycles per
second were found in the involved male (and his brother iv, 6 as well) and
about 35 cycles per second in the female carrier.
color-vision abnormalities on the Farnsworth-Munsell 100-Hue Test
(a greater than normal number of errors and a deuteranomalous axis)
and on the Nagel anomaloscope (a wider than normal Rayleigh equa-
tion with displacement toward the green end of the instrument). All
other visual functions were normal.
PARTIAL COLOR BLINDNESS (DEUTAN AND PROTAN DEFECTS)
The characteristics of partial red and green color-vision defects (pro-
tanopia, protanomaly, deuteranopia, deuteranomaly) are well known.
The two most frequently reported abnormalities in female carriers are
abnormal performance on the anomaloscope and decrease in sensitivity
to red light. The two abnormalities emphasized on the anomaloscope
X-Chromosomal-LinkedDiseases t-1543
in both green (deutan) and red (protan) defect carriers are an ab-
normally wide equation (pathological scatter) and an equation dis-
placed slightly toward red in protan carriers and toward green in
deutan carriers.26-31 The other most frequent abnormality is noted in
protan carriers and is called Schmidt's sign after its discoverer.2 This
defect consists of a darkening of the red end of the spectrum and is
demonstrated by a shift of the photopic spectral luminosity curve
toward the violet end of the spectrum. The maximum sensitivity is
displaced about half-way between the normal position and the position
typical for protan males. This sign is not correlated with other findings
and in fact may occur with completely normal color performance on
all other tests.
Other abnormalities reported in a few carriers include:26'27'28 (1)
errors on the pseudoisochromatic plates; (2) decreased differential
saturation thresholds, particularly for red in protan carriers and for
green in deutan carriers; (3) exaggerated contrast on the anomalo-
scope in three carriers of protanopia; (4) elevated hue differential
thresholds, mainly in blue and blue-green spectral areas in a carrier of
protanopia and in one of deuteranomaly; and (5) deviation of the
luminosity quotient (ratio of luminosity of green and red in the equal-
energy spectrum) in both deutan and protan carriers.3>33 Occasionally
the color-vision abnormality is as severe as in affected males.
Examples of abnormalities on the Nagel anomaloscope in carriers
of protan defects from five families we studied (Figure 5) are shown
in Table 1. The abnormalities include a slight, but definitely abnormal,
matching equation in four of nine carriers, an abnormally wide match
range in three carriers, and an abnormal minimal brightness point in
two carriers. We have also detected brightness abnormalities in protan
carriers by using red-light thresholds. We found a significant elevation
of the absolute red-light threshold at five degrees retinal eccentricity
in seven of eight protan carriers studied.13 The elevations were of the
same order in protanopes, protanomals, and their female relatives. In
another study, the fovea and four peripheral retinal areas were tested
with a red light before the occurrence of the rod-cone break.34 Six
female carriers of protanopia were tested and elevated thresholds were
found at the fovea in all carriers, and in some peripheral retinal areas
in two carriers (Figures 6, 7, and 8). However, the thresholds for
carriers were far below those obtained from six protanopic males. In
neither of the above two studies was the degree of threshold elevation
related to the performance of carriers on other color-vision tests.
In another study we used the Farnsworth-Munsell 100-Hue test for
544 Alex E. Krill
PROTANOPIA
I
IL b
a. b. C. d. e. f. 9.
a. b. c. d. e. t. 9. h i. j.
FAMILY I
I ( * I([
a b. a. b.
a. b. c. d. a. b. c. e.
a. b. a.
FAMILY 2 FAMILY 3
PROTANOM-ALY
I~~ ~ ~
a b c. d o. b.
o. h c d- e. f. o. b. c. d.
= A m O0
a'. b- a. b. c.
FAMILY 4 FAMILY 5
LEGEND
1,=MALES OR FEMALES G-EXAMINED NORMAL O NO INFORMATION
*EAFFECTED REPORTED NORMAL V/z EXAMINED
INDIVIDUAL 1 REPORTED AFFECTED W STATUS UNCERTAIN
)-zCARRIERS
FIGURE 5
Pedigrees of 3 families with protanopia and 2 with protanomaly.