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Studies of AlcaptonuriaA Genetic Study of 58 Cases Occurring in Eight Generations of Seven Inter-related Dominican Kindreds.

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Arthritis and Rheumatism
o$cial juurnul of the grnerican Rheumatismassociation
APRIL, 1961
VOL. IV, NO. 2
Studies of Alcaptonuria: A Genetic Study of 58 Cases
Occurring in Eight Generations of Seven
Inter-related Dominican Kindreds
A study of the inheritance patterns of Esseva effectuate in le Republica Dothe molecular disease alcaptonuria has minican un studio del rete de relationes
been conducted in the Dominican Re- hereditari de occurrentias del morbo
public. A total of 58 authenticated cases molecular alcaptonuria. Usque hodie, un
have been obsewed to date, and addi- total de 58 confirmate casos ha essite
tional cases undoubtedly exist. Viewed obsewate. Casos additional existe sin
collectively, all of the obsewed data, dubita. Reguardate como gruppo collecincluding instances of apparent, though tive, le datos colligite-incluse tales que
spurious, dominant transmission, appear poterea, superficialmente, indicar ufi
to be adequately explicable on the as- transmission dominante-es apparentesumption that the alcaptonuria allele mente explicabile super le base del
behaves in these kindreds as if it were these que le allelo de alcaptonuria se
comporta in iste consanguineos como si
a simple, rare autosomal recessive.
ill0 esseva un simple e rar recessivo
LCAPTONURIA, the &st of the genetically determined “inborn errors of
metabolism” or “molecular diseases” to be described in man,l is defined
by the abnormal urinary excretion of the otherwise normal intermediary metabolite, homogentisic ( 2,Sdihydroxyphenylacetic) acid. The disorder arises in
consequence of an inherited absence of the enzyme homogentisicase2 and is
an integral part of a true syndrome characterized initially by homogentisic
aciduria, or alcaptonuria, then ochronosis and later by pronounced arteriosclerosis and osteoarthriti~.~-~
In the great majority of reported instances, the disorder is inherited as if in
consequence of a simple autosomal recessive gene substitution. In a number of
From the Division of Orthopaedic Surgery, The Johns Hopkfns University School of
Medicine and the ]ohm Hopkins Hospital, Baltimore, Md.
Aided b y a grant (A-2642) from the Nntional Institute of drthritis and Metabolic Diseases,
National Institutes of Health, Education and Welfare.
Prwnted, in part, at the Sixth Interim Scientific Session, American Rheumatism Association, Hen* Ford Hospital,Detroit, Michigan, December 11, 1959.
,E *.'
,. c.s*ic.o9"
Hornogantlslc ocldurio
t Aieoptonurio)
Fig. 1.-Summary of intermediary metabolic pathway of the amino acid phenylalanine. Inability to disrupt the benzene ring of homogentisic acid, arising in consequence of the inherited absence of the enzyme homogentisic acid oxidase, results
in the development of the alcaptonuria syndrome.
families, however, the observed data appear to contradict this view.lOill These
include the family generally considered the sole unequivocal instance of dominant inheritance in the literature reported by Pieter12 in 1925 and the cases
reported initially by Osler, by Smith and by ourselvesI3 in which instances of
direct transmission from affected parent to offspring had been observed.
The subsequently discovered fact that our family 111 derived from the same
geographical area as the family studied by Pieter some twenty-five years earlier
suggested the obvious possibility that the two families were actually inter-related. Accordingly, an investigation of all known members of the two pedigrees
Fig. 2.-Costo-chondral
junction of a patient with the alcaptonuria syndrome.
The cartilage is densely pigmented 'and, in the central portion, presents evidence of
degenerative changes. Bone is entirely devoid of pigment.
was conducted in an attempt to provide a means whereby the various genetic
postulates could be better evaluated.
Details of the clinical, laboratory and epidemiologic methods employed are presented
elsewherd4 in connection with family data on the first 47 alcaptoniuic subjects. Additional
pedigree data, encompassing an additional 11 patients, or a total of 58 alcaptonuric subjects in eight generations of seven highly inter-related families in the Dominican Republic,
are presented in figure 4 (which because of page size limitations is not presented here;
it will be available in the reprints ) .
It is readily apparent that numerous inter-relationships exist between the
various members of the seven study kindreds. In general, however, there is a
division of the seven into two more or less defined groups, one being represented by kindreds 1, 2 and 3 and the other encompassing kindreds 4-7.
Although inextricably related to them, these latter kindreds are more or less
socially distinct from the kindreds 1, 2 and 3. Individuals in kindreds 1, 2 and
3 are phenotypically Caucasians, while individuals in kindreds 4 through 7
present an admixture of racial types, with a greater resemblance to darkskinned mestizo15 types. (Data on the blood proteins of the present study kindreds and similar data on a representative Dominican population not related
to these kindreds will be published separately.) * Furthermore, extramarital
OBoyer, S. H.,and Milch, R. A. A new G, determinant, G,,,*b, in colored populations.
American Soc. Human Genetics, Memphis, Tenn., April, 1960.
Fig. 3.-Roentgenograms of the dorsal (lateral view) and lumbar (anteroposterior view) spine in a patient with the alcaptonuria syndrome. Same patient
(aged 35 years) as in figure 2. Calcification and “vacuum signs” of the intervertebral
disc spaces are well demonstrated, as is the eburnation of the contiguous bony
surfaces of the vertebral bodies.
matings were both relatively and absolutely greater in the kindreds 4 through
7 and correspondingly, the incidence of alcaptonuria was greater in these latter
kindreds than in 1, 2 and 3. (52 of the 58 cases indicated here, including all of
the instances of direct transmission of the disorder from parent to child, have
been observed in kindreds 4 through 7.)
Kindreds 1, 2 and 3, comprising affected individuals V-2, V-5, V-12 and V-13
and VI-4 and VI-5, pose no especial interpretative difficulties in terms of the
currently revised and expanded data. The allele is clearly not manifested as a
simple dominant. In fact, the observed ratios of affected to nonaffected individuals in any given family group of the pedigree closely correspond to
what would be expected if in fact the allele were manifested as a simple, autosoma1 recessive.
Kindreds 4 through 7,*on the other hand, present ct somewhat more complex situation. These too, however, can be readily accounted for on the basis
of the simple, recessive hypothesis. In those instances in which neither parent
was affected, and hence, in which both of whom were phenotypically normal,
the observed frequency data closely approximate that to be expected (0.25)
if it be assumed that both parents were heterozygous for the abnormal allele.
Similarly, where only one parent of affected children is also affected, the ob*An apparently isolated eighth kindred presumably related to both kindred 6 and 7 ‘was
originally reported.14 It has been ascertained that this former kindred is in fact related to
both 6 and 7 and is related on both the maternal and paternal sides of the family. Hence,
this family group cannot further be considered a distinct entity; accordingly, only seven
kindreds have been identified here.
served frequency ratios are of an order of magnitude closely corresponding to
that to be expected (0.50) if it be assumed that the union involved one individual phenotypicially normal but genotypically heterozygous for the abnormal allele with another who was homozygous for the abnormal allele.
Theoretically, the likelihood would be greatest that phenotypically normal
individuals in these inbred isolates are genotypically heterozygotes rather than
homozygotes for the normal allele. This is further supported by the fact that
all of the cases of apparent dominance and about 90 per cent of all the cases of
alcaptonuria noted here have occurred in precisely the same kndreds. The
apparently suggested hypotheseslOJ1to account for the seemingly anomalous
behavior of the “alcaptonuric gene” in certain family groups thus appear to
be unnecessary. Indeed, all of the observed data can be readily accounted for
by the assumption of the simple allele hypothesis.*
A similar interpretation can be applied to the extensive but insufficiently
documented data reported within the past several years from Czechoslovakia.le
Superficially viewed, the data there reported are quite comparable to those
reported here. Since details of the mating inter-relationships are almost entirely omitted, however, a definitive conclusion cannot be drawn.
Viewed collectively, therefore, all of the observed data, including instances
of apparent dominant transmission, appear to be adequately explicable on the
assumption that the alcaptonuria allele in this, as in other pedigrees, behaves
as if it were a simple, rare, autosomal recessive.
A great many people have contributed to the conduct of the present study. Many are not
named here. To them, however, as well as to those specificially mentioned, the writer
wishes to express his sincere thanks and heartfelt gratitude. In particular, he wishes to
express his great indebtedness to Drs. Henry Milch, Heirberto Pieter, Lolita de la Huerga,
Raul Alberty and Robert Robinson for their constant aid, guidance and stimulation; to Sr.
Manuel de Moya Alonzo and Sra. Grisela Castillo de Minino and to Messrs. Robert Johnson and Richard Murray for their invaluable assistance and especially to the many members
of the study kindreds who cooperated so freely in providing the necessary family data.
1. Garrod, A. E.:Inborn Errors of Metabolism, ed. 2. London, H. Frowde,
Hodder and Stoughton, 1923.
2. LaDu, B. N., Zannoni, V. G., Laster,
L., and Seegmiller, J. E.: The nature
of the defect in tyrosine metabolism
in alcaptonuria. J. Biol. Chem. 230:
251-260, 1958.
3. Milch, R. A., Walker, W. G., and Yard-
ley, J. H.: Studies of alcaptonuria:
Renal, function and structure in a
patient with ochronosis. Submitted
for publication.
4. -, Titus, E. D., and Loo, T. L.: Atmospheric oxidation of hornogentisic
acid: Spectrophotometric studies.
Science 126:209-210, 1957.
5. Osler, W.: Ochronosis: The pigmenta-
‘Others have called attention to the observation that, in most published pedigrees, there
is a somewhat higher proportion of affected males than femdes. Harris17 has felt that
this is probably purely fortunitous and that the sex ratio would tend to approach one in
more extensive pedigrees. This appears to be true on the basis of the inheritance data in
the present kindreds. There is no evidence of sex-linkage and die ratio of affected males to
affected females is close to one.
tion of cartilages, sclerotics and skin
in alkaptonuria. Lancet l:lO-ll, 1904.
6. Milch, R. A.: Studies on the pathogenesis of collagen tissue changes in alcaptonuria. Surg. Forum II :448-449,
7. --, and Robinson, R. A.: Studies of
alcaptonuria: content and density of
the water and solid phases of ochronotic cartilage, J. Chron. Dis. 12:409416, 1960.
8. Knox, W. E.: The metabolism of
phmylalanine and tyrosine. In McElroy, W. D., and Glass, B., Eds.:
Amino Acid Metabolism. Baltimore,
The Johns Hopkins Press, 1955.
9. Virchow, H.: Ein fall allgemeiner
Ochronose der Knorpel und Knorpelaehnlichen Theile. Virchow’s Arch. f.
path. Anat. 37:212219, 1866.
10. Hogben, L., Worral, R., and Zieve, I.:
The genetic basis of alcaptonuria.
Proc. Roy. SOC. Edinburgh 52:264295, 1W2.
11. Milch, R. A.: Direct inheritance of alcaptonuria. Metabolism 4:51%518,
12. Pieter, H.: Une famille d‘alcaptonuriques. Presse mbd. 33:1310, 1925.
13. Milch, R. A., and Milch, H.:Dominant
inheritance of alcaptonuria, Acta
Genet. 7:17%184, 1957.
14. -: Studies on alcaptonuria: Inheritance
of 47 Cases in eight highly inter-related Dominican kindreds. Am. J. Human Genet. 12:76-85, 1980.
15. Alvarez, J. de J.: Studies of the A-B-0,
M-N and Rh-Hr blood factors in the
Dominican Republic, with special reference to the problem of admixture.
Am. J. Phys. Anthropol. 9:127-148,
16. Sitaj, S., Cervenansky, J., and Urbanek,
T.: Alkaptonuria a Ochronoza. Vydavatel’stvo Slovenske j Akademie Vied.,
Bratislava, 1956.
17. Harris, H.: Personal communication.
Robert Austin Milch,M.D., Chief Resident Orthopaedic Surgeon, The ]ohm Hopkins Hospital and Research Fellow in
Orthopedic Surgey, The ]ohm Hopkirts University School of
Medicine, Baltimore, Md.
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