502
The authors wish to express their appreciation to Dr. H. A. Hunter, Professor of Oral Pathology,
Faculty of Dentistry, University of Toronto, for
his assistance with the histological study of the
deciduous tooth; and also to Dr. J. R. Bensimon for his assistance in the compilation of the pedi-gree.
REFERENCES
1. Oliver, W. J., et al.: Hypoplastic enamel in nephrosis. PEDIATRICS, 32 :399, 1963.
2. Shafer, W. C., Hine, M. K., and Levy, B. M.:
A Textbook of Oral Pathology. Philadelphia:
w.
B. Saunders, 1961, p. 39.3. Engfeldt, B., Bergman, C., and Hammarlund-Essler, E. : Studies on mineralized dental tissues. I. A microradliographic and auto-radiographic investigation of teeth and tooth germs of normal dogs. Exp. Cell Res., 7:381, 1954.
4. Hals, E. : Dentin and enamel anomalies:
histo-logic observations. In Genetics and Dental
Health, Witkop, C. J., Ed. New York:
McGraw Hill, 1961, p. 246.
5. Weinmann, J. R., Svoboda, J. F., and Woods, R. W. : Hereditary Disturbances of Enamel
Formation and Calcification. J. Amer. Dent. Assoc., 32:397, 1945.
6. Darling, A. I. : Some observations on
amelo-genesis imperfecta and calcification of the
dental enamel. Proc. Roy. Soc. Med., 49:
759, 1956.
7. Witkop, C. J.: Hereditary defects in enamel
and dentin. Acta Genet., 7:236, 1957.
8. Schulze, C. : Acta Cenet., 7:231, 1957.
9. Mohr, 0. L. : Woolly hair a dominant mutant character in man. J. Hered., 23:345, 1932. 10. Cates, R. R. : Human Genetics. Vol. 2. New
York: Macmillan, 1957, pp. 1351-1359.
Early
Diagnosis
and
Treatment
of
Homocystinuria
In the three years since homocystinuria
was first described by Field and Carson and
their 2 it has become evident that
this newly discovered inborn error of
methio-nine metabolism may be less rare than had
originally appeared. At least 20 cases of
homo-cvstinuria have been reported2S to date from
the United Kingdom and the United States.
We ourselves have encountered 8 children
with homocystinuria in 3 unrelated families
in British Columbia.9 As interest in the
dis-ease increases and efforts to detect it are
more routinely made, it is possible that
homo-cystinuria may be found to approach
phenyl-ketonuria in frequency among the
biochemi-cal causes of mental defect.
Since homocystinuria involves an enzymatic
block in the metabolism of an essential amino
acid methionine, limitation of the dietary
in-take of methionine during infancy and
child-hood might produce beneficial clinical results
comparable to those of the low-phenylalanine
diet in phenylketonuria. Any appreciable
cor-rection of the derangement in sulfur amino
acid metabolism in an infant with
homocys-tinuria
would
be
important to achieve, sincethe infant not only is likely to become
men-tally defective, but will later suffer dislocated
lenses and skeletal abnormalities, and may
die of major intravascular tliromboses.
We wish at this time to report our
experi-ence in the diagnosis of a case of
homocy-stinuria in the newborn period, and in the
successful bypassing of one part of the
bio-chemical error through treatment of the
in-fant with a low-methionine diet. Whether or
not this treatment will prevent mental defect
in our patient may take several years to
de-termine. We hope, meanwhile, that this
pre-liminary report may stimulate other
physi-cians to test newborn infants routinely for
homocystinuria, and to try prompt dietary
treatment on cases detected.
CASE REPORT
C. S., a baby boy, was the product of a normal pregnancy and delivery. Birth weight was 3.5 kg, and the infant appeared in good condition. Two
older siblings had homocystinuria, and it was
realized in advance that this infant might prove
to have the disorder. Cord blood was saved for
later examination, and a urine specimen was ob-tamed at the age of 4 days, as well as a specimen of venous blood on the fifth day of life. The urine excreted on the fourth day of life, as well as all subsequent urine specimens examined prior to in-stitution of a low-methionine diet, yielded strongly
positive cyanide-nitroprusside screening tests, and
the presence of homocystine was readily
demon-strable on two-dimensional paper chromatography. The concentrations of methionine and other amino
acids in the infant’s plasma were determined on a
Technicon amino acid analyzer. Serum methionine concentration in cord blood was found to be 0.45
mg/100 ml. This had risen to 19.30 mg/100 ml
on the fifth day of life, and to 27.80 mg/100 ml
on the ninth day of life. Plasma methionine
con-centrations in normal newborn infants are
re-ported to be less than 0.6 mg/100 mI.10
EXPERIENCE AND REASON-BRIEFLY RECORDED 503
TABLE I
PLASMA AMINO ACIDS IN RELATION TO VARIATIONS IN DIET
Age (days) , . JT eight (kg) . Diet Supplemental Dietary . Cystine (ing/kg/day) Plasma . . * Methionine Plasma . * Cysti ne Plasma FIo,,io-. cystlne* . Urinary . liomocystine
Birth 3.5 0.45 Tr.t Of
4 Cow’s milk None + +
5 formula 19.30 0.24f Tr.t
9 27.80 Of .27f ++++
16 4.0 28.7O 0 .50
++++
22
Low-methionine 13 .95 0.79 Tr. +formula
‘29 4.0 100 4.99 0.3 .c21
+
35
Breast milk 4.38 0.53 0+
41 4.4 150 4.06 0.80 ‘Fr.
+
53
63 69 t 5.0) Low-methionine formula 20O 1.801.55
0.52
0 .9’2
0
0
0
0
* Values expressed in mg per 100 ml plasma. Tr. indicates amino acid present, but in an amount insufficient for
accurate quantitation. Normal values for plasma methionine in newborn infants are below 0.60, and for plasma
cystine range between 0.70 and c2.OO.b0
t Values for cystine and homocystine shown are probably too low, due to delay in deproteinizing specimens.
milk formula since birth, was admitted to the Health Centre for Children, Vancouver General Hospital, on the sixteenth day of life, and at this time was started on a special low-methionine for-mula composed of soy bean protein, to which corn oil and dextrimaltose had been added.#{176} The in-fant was given sufficient formula to provide 125 calories per kilogram per day, and sufficient
L-cystine was added to each day’s formula to pro-vide the infant with an additional 100 mg of cystine per kg body weight. After 12 days on this low-methionine diet, the infant’s plasma methio-nine concentration had fallen to 4.92 mg/100 ml, and only traces of homocystine could be detected
in the urine.
Because the infant had failed to gain weight, the special low-methionine diet was temporarily discontinued at this point, and was replaced by breast milk enriched with sufficient L-cystine to provide an additional 100 mg/kg/day. During 13 days on human milk, the infant gained 280 gm
in weight, but the plasma methionine concentra-lion failed to drop below 4 mg/100 ml. The breast milk diet was then discontinued, and the
infant was again fed the special low-methionine
product. Sufficient L-cystine was added during
a Product 3200-K, Mead Johnson & Co.,
Evans-ville, Indiana.
preparation of the formula to provide 150 mg/ kg/day in addition to that present in the soy bean protein isolate. Later, supplemental cystmne was further increased to 200 mg/kg/day. Resump-tion of the special low-methionine diet resulted in eventual lowering of the plasma methionine concen-tration to 1.55 mg/100 ml, and the infant gained weight satisfactorily.
The rise and fall of blood methionine concen-trations, and the presence or absence of homo-cystine in plasma and urine, are shown in Table I, in relation to the diets consumed by the infant.
At the time this is written, C. S. is 10 weeks old. His weight has increased to 5.0 kg. He is
alert, lifts his head when prone, follows objects
and persons with his eyes, and smiles readily in response. He is still somewhat tense and tremu-bus, as he was at 16 days of age, and he has
about 6 beats of ankle clonus. Otherwise he
pre-sents no neurological abnormalities. An
electroen-cephalogram at 9 weeks of age showed no
ab-normality except for a sharp phase reversal of
low amplitude over the left parietal region. No
abnormalities of the lenses, in liver size, or of the bones and joints have been detected so far. The
infant has now been discharged from hospital to
his parents, and is to continue on the
504
with periodic checks of blood methionine and
urinary homocystine.
COMMENT
Our experience with this homocystinuric
infant makes several things apparent. In the first place, routine screening of those infants
f
ed a cow’s milk formula for homocystinuriaon discharge from the newborn nursery, or
shortly thereafter, should be effective in
de-tecting the disease. This could readily be
ac-complished by collecting a urine specimen
and performing the cyanide-nitroprusside
screening test.4 The concentration of
methio-nine in blood evidently rises rapidly after
birth in the homocystinuric infant, and should
be high enough on discharge from the
nur-sery to be detected on a blood spot on filter
paper by the one-dimensional paper
chroma-tographic screening test devised by Efron et
al.12 Because of the lower content of
methio-nine in human milk as compared to cow’s
milk, it is likely that the diagnosis of homo-cystinuria might be missed by these screen-ing tests in breast-fed infants.
It is evident that institution of a
low-methionine diet can largely correct the
ele-vated tissue concentrations of methionine
which occur in young homocystinuric infants.
Whether or not this therapy will prove
suffi-cient to prevent the mental defect and other
harmful results of the disorder remains to
be determined. The special low-methionine
formula our patient is receiving contains 26 mg of methionine per 100 ml of normal
dilu-tion. Human milk is reported to contain 6 to
36 mg/100 ml, and cow’s milk 50 to 140
mg/100 ml.13
If the mental defect of homocystinuria is
due to the effect of elevated tissue
concen-trations of methionine on passage of other
amino acids into the rapidly growing brain,
or if it is due to toxic effects of as yet
un-identified metabolites of methionine on the
brain, then a low-methionine diet might
prove beneficial. After diagnosis of the
dis-order in a newborn infant, and until a
spe-cial low-methionine formula can be obtained,
a diet of breast milk would be preferable to
one of cow’s milk. If the mental defect of
homocystinuria proves to be due to absence of cystathionine from brain, secondary to the
basic defect in cystathionine synthetase,6”
use of a low-methionine diet would be
ex-pected to be ineffective in preventing mental
defect, but might still prevent the other
seri-ous clinical manifestations of the disease.
We have not attempted to give
cystathio-nine to our patient because of the prohibitive expense of L-cystathionine, and because this
amino acid has a high renal clearance and
may not even penetrate into the brain when
supplied orally. On the other hand,
admin-istration of supplemental L-cystine in the
treatment of homocystinuria seems strongly
indicated. Since the homocystinuric patient
cannot form cysteine from methionine, the
former becomes an essential amino acid.
Westa1l’ found it necessary to provide 150
mg/kg/day of L-cystine to a homocystinuric infant under treatment with a low-methionine diet in order to achieve normal cystine con-centrations in plasma. In our own patient, plasma cystine concentrations were low, and
weight gain was slow initially, possibly due
to administration of insufficient supplemental
cystine.
ADDENDUM
At the age of 6 months, C. S. continues to show
normal growth and behavioral development. Neuro-logical examination, slit lamp examination of the eyes, and roentgenograms of the bones disclose no abnormalities. Plasma methionine concentrations, however, have recently ranged between 4 and 7 ing per 100 ml, despite further reduction of dietary
methionine, and a small amount of homocystine is regularly detectable in urine.
SUMMARY
Homocystinuria was diagnosed in a
new-born infant by detection of homocystine in
urine on the fourth day of life, and by the
demonstration of a marked elevation of serum
methionine concentration on the fifth day.
Treatment with a special low-methionine diet has reduced the concentrations of methionine
in blood to near-normal levels. This
meta-bolic disease should be searched for by
rou-tine screening of newborn infants, and may
possibly respond favorably to dietary therapy.
THOMAS L. PERRY, M.D.
HENRY C. DUNN, MB., M.R.C.P.
SHIRLEY HANSEN
LYNNE MACDOUGALL
PATRICK D. WARRINGTON
Departments of Pharmacology
and Paediatrics
The University of British Columbia
EXPERIENCE AND REASON-BRIEFLY RECORDED 505
We thank Dr. Wilfred C. Chin of Kamloops, B.C., for referring the patient to us; Dr. Warren
M. Cox, Jr., Mead Johnson Research Center,
Evansville, Indiana, for generously supplying the
experimental low-methionine diet; and Dr. R. C.
Westall, University College Hospital Medical
School, London, for his helpful advice.
Supported by grants from the Medical Research
Council and the Department of National Health
and Welfare, Canada.
REFERENCES
1. Field, C. M. B., Carson, N. A. J., Cusworth, D. C., Dent, C. E., and Neill, D. W.: Homocystinuria. A new disorder of metab-olism. Abstract Tenth Internat. Congr. Pediat., Lisbon, 1962, p. 274.
2. Carson, N. A. J., Cusworth, D. C., Dent, C. E., Field, C. M. B., Neill, D. W., and
Westall, R. C. : Homocystinuria: A new inborn error of metabolism associated with mental deficiency. Arch. Dis. Child., 33: 425, 1963.
3. Komrower, C. M., and Wilson, V. K.:
Homo-cystinuria. Proc. Royal Soc. Med., 56:996, 1963.
4. Cerritsen, T., and Waisman, H. A.:
Homo-cystinuria, an error in the metabolism of methionine. PEDIATRICS, 33:413, 1964. 5. White, H. H., Thompson, H. L., Rowland,
L. P., ‘Cowen, D., and Araki, S.:
Homo-cystinuria. Trans. Amer. Neurol. Ass., 89: 24, 1964.
6. Mudd, S. H., Finkelstein, J. D., Irreverre, F.,
and Laster, L. : Homocystinuria: An
en-zymatic defect. Science, 143: 1443, 1964.
7. Finkelstein, J. D., Mudd, S. H., Irreverre, F.,
and Laster, L. : Homocystinuria due to cystathionine synthetase deficiency: The
mode of inheritance. Science, 146:785, 1964.
8. Carson, N. A. J., Dent, C. E., Field, C. M. B.,
and Caull, C. E. : Homocystinuria. J.
Pediat., 66:565, 1965.
9. Dunn, H. C., Perry, T. L., and Dolman, C. L.:
Homocystinuria, a recently discovered cause
of mental defect and cerebrovascular
throm-bosis. Neurology. In press.
10. Chadimi, H., and Pecora, P. : Plasma amino
acids after birth. PEDIATRICS, 34: 182, 1964. 11. Dickinson, J. C., Rosenbium, H., and
Hamil-ton, P. B. : Ion exchange chromatography
of the free amino acids in the plasma of the newborn infant. PEDIATRICS, 36:2, 1965.
12. Efron, M. L., Young, D., Moser, H. W., and MacCready, R. A. : A simple
chromatograph-ic screening test for the detection of disorders of amino acid metabolism. A technic using whole blood or urine collected on filter
paper. New Engl. J. Med., 270:1378, 1964.
13. Spector, W. S., Ed.: Handbook of Biological
Data. Philadelphia: W. B. Saunders, 1956,
p. 199.
