Phenylketonuria variants in Ontario ADVISORY COMMITTEE ON INBORN ERRORS OF METABOLISM * TO THE ONTARIO MINISTRY OF HEALTH

Since mass screening of the newborn population for phenyikotonuria (PKU) by the Guthrie test was begun in Ontario in Juiy 1965 many variants of PKU have been recognized in the 96 to 970/* screened. Seventy-one cases of classic PKU were detected (four were missed). Of 48 cases of persistent hyperphonylalaninemia discovered, 18 were classified as atypical PKU and 30 as persistent benign hyperphenylalaninemia. Numerous infants with transient hyperphenylalaninemia (initial values over 10 mgldl in 12), in many instances the result of transient neonatal tyrosinomia, were discovered. There was a slight predominance of males. Serum phenylalanino values of up to 15 mg/dl seemed to be harmless to the developing brain. A survey of 67247 adults in the general population revealed I person with PKU and I with persistent benign hyporphonylalaninemia; both had normal intelligence quotients. Of 1548 mothers of retarded children tested, none had hyporphenylalaninemia. Depuis qu'un systeme de depistage do masse, utilisant le test do Guthrie, a ste institu6 on Ontario pour detector Ia phenylcetonurie (PCU) choz los nouveaux-nes, plusiours varlantos do Ia PCU ont ste reconnuos chez los 96 a 970/o dos sujets test6s. Soixanto-onzo cas do PCU classique

'Members: W.B. Hanley, MD; M.R. Jenner, MD; R.S. Khazen, MD; M.W. Partington, MD; WJ.A. Percy, MA; John Rathbun, MD (deceased); Jean F. Webb, MD and Donald T. Whelan, MD. From the departments of pediatrics, University of Toronto, University of Western Ontario, McMaster University and Queen's University Presented in part to the American Pediatric Society, Atlantic City, New Jersey, Apr. 29 to May 2, 1970, and to the Canadian P.diatric Society, Calgary, July 22, 1972 Reprint requests to: Dr. R.S. Khazen, Ontario Ministry of Health, Special health services branch, Fifth floor, 15 Overlea Blvd., Toronto, ON M4H 1A9

ont et6 d6cel6s (quatro ont 6chapp6 au depistage). Parmi los 48 cas d'hyporphenyialaninemie d6couverts, 18 ont 6t6 classifies comme des PCU atypiquos ot 30 comme des hyporphenyialanin6mlos porsistantos benignos. Nombreux nourrissons presontant uno hyperphenylalanin6mio passagero (12 avec dos valeurs superiouros a 10 mg/dl), lo r6sultat, dans bion des cas, d'une tyrosinemie passagero, ont 6te d6coles. On a constat6 uno l6gere predominance dos garqons. Des concentrations seriquos on phenylalanino allant jusqu'a 15 mg/dl n'ont pas somble affecter defavorabloment lo developpoment cer6bral. Uno etude conduito choz 67247 adultos pris dans Ia population g6n6ralo a r6v616 Ia presonco dune personne attointo do PCU ot d'uno autre pr6sontant uno hyperphenyialanin6mio porsistanto b6nlgno; los deux avalont un quotient intolloctuel normal. Parmi los 1548 mores d'enfants rotardes qui ont subi Is test, aucune no souffrait d'hyperphenylalaninemio. Prior to 1963 the frequency of phenylketonuria (PKU) in the total population in North America was estimated to be 1/24 0001,1 In the years 1963 to 1965 widespread screening for PKU among newborn infants was begun and a frequency of 1/12 000 was reported.3'4 Screening identified, in addition to "classic" PKU, variants of hyperphenylalaninemia that had previously gone undetected because in most instances profound mental retardation did not occur despite an unrestricted diet.5 These variants accounted for 5 to 55% of all cases of persistent hyperphenylalaninemia, depending on the population studied.6'7 In North America the ratio appears to be about one variant case to two cases of classic PKU."' In France and Switzerland the ratio is

close to 1:1 6 as in French Canada,7 while in Scotland the ratio is about 1:6, in England 1:8 and in Poland 1:20.6 Classic PKU in Israel is limited almost exclusively to non-Ashkenazic Jews and Arabs.7 The variants are difficult to classify at present because a particular term means different things to different authors. Some of the names given the variants include atypical PKU, PKU variant, hyperphenylalaninemia without PKU, persistent hyperphenylalaninemia, mild PKU, normal PKU, soft PKU, benign hyperphenylalaninemia, partial PKU, neonatal phenylalaninemia, occult PKU, latent PKU and transient hyperphenylalaninemia. 9-14 It is generally agreed that the variants represent a number of different genetic and biochemical entities that cannot be distinguished from each other accurately by present means. Some possibilities suggested include different homozygous phenotypes, double heterozygotes for mutant alleles at a common gene locus or different loci, modifier genes and genetic compounds.' This is a report of the results of three surveys searching for hyperphenylalaninemia: * Survey 1: the Ontario neonatal screening program. Neonatal screening for PKU by the bacterial inhibition assay of Guthrie15 has been carried out since July 1965 in the Province of Ontario. * Survey 2: conducted in a group of randomly selected adults in the general population. * Survey 3: conducted in mothers who had at least one retarded child. Classification of PKU and its variants All infants with elevated values of serum phenylalanine (over 4 mg/dl) were categorized by a modification of Scriver's classification7 (Table I). The potentially damaging forms of hyper-

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phenylalaninemia (those thought to need dietary therapy) were labelled phenylketonuria (PKU). Mild forms, those generally thought to be harmless to the developing brain (and thus not needing dietary therapy), were labelled benign hyperphenylalaninemia. The criteria for classification are shown in Table II. PKU Patients with classic PKU usually have a rapid, early increase in their serum phenylalanine concentration; by 1 week the value is over 50 mg/dl. Months later, when they are given

phenylalanine loading tests, the value increases from the normal or modestly increased values produced by the lowphenylalanine diet to at least 35 mg/dl. Response to dietary therapy is relatively slow; desired blood values are reached in 7 to 10 days. Daily phenylalanine requirements are moderately high at first but decrease in a few months. Urinary metabolites are present early but phenylpyruvic acid may not appear for 6 weeks. Phenylalanine loading tests show a homozygote pattern in the patient'6 and a heterozygote pattern in both parents. The parents have phenylalanine/tyrosine (PIT) ratios of more than 1 .2.'. Phenylalanine hydroxylase activity in liver is zero.'8"' "Atypical" PKU describes the condition of a small group of less severely affected patients who have a high dietary tolerance for phenylalanine. Some, if not all, of these patients need dietary therapy for at least a few months. The serum phenylalanine concentration increases more slowly and peaks at lower values, both neonatally and with loading, than in patients with classic PKU. Tolerance to phenylalanine is much higher; if atypical PKU is not suspected, phenylalanine deficiency may develop rapidly when dietary therapy is begun. Liver enzyme activity is between 0.1 and 5% of normal.". Benign hyperphenylalaninemia There are transient and persistent forms. One rare type of transient hyperphenylalaninemia occurs in infants born to women with untreated PKU; serum phenylalanine values in the infant may be elevated for 1 to 2 days. TranMent neonatal tyrosinemia" may result in secondary hyperphenylalaninemia, 22 which can last from 5 to 21

days and is usually associated with serum phenylalanine values of 4 to 10 mg/dl. This condition is more likely to occur in immature babies and in those fed high-protein formulas. A third category, transient phenylalanine transaminase deficiency," may or may not exist.7'23 A fourth, "idiopathic" transient hyperphenylalaninemia, occasionally lasts for several months.'4 In persistent benign hyperphenylalaninemia the serum phenylalanine values may initially be as high as 40 mg/dl but they soon decrease to 5 to 15 mg/dl. Urine metabolites are infrequently detected and only when the serum phenylalanine values are higher. Liver enzyme activity is 5 to 20% of normal."-20 It is sometimes difficult in the first few weeks to categorize each individual case accurately and often it is only after repeated observations and testing, including dietary phenylalanine challenges, over the first 2 to 3 months, that a final decision can be made. Differences in classification Many different attempts have been made to classify PKU and its vanants..2' The main divergence from ours in the various classifications is that many authors label as having "atypical PKU" all children with hyperphenylalaninemia other than those with classic PKU.4'2-3' Some reserve the term "atypical PKU" for the condition of the few who have the biochemical features of classic PKU but normal intelligence although they are untreated.27'32'33 Blaskovics, Schaeffler and HackM have outlined a classification of hyperphenylalaninemias based on response to an oral load of phenylalanine (180 mg/kg). The plasma phenylalanine concentration that divides PKU from benign hyperphenylalaninemia is controversial, ranging from 8 mg/dP.'3 to 20 mg/ dl.4"""37'3' Survey methods Survey 1 Approximately 96% of newborn infants born in Ontario between July 1965 and July 1975 were screened for hyperphenylalaninemia by the Guthrie test.'5 The diagnosis was confirmed by measuring the concentrations of serum phenylalanine3' and tyrosine and by testing urine for phenylpyruvic acid and orthohydroxyphenylacetic acid. Survey 2 A total of 67 247 serum samples selected at random from specimens submitted from the general adult population to the serologic department of

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the provincial laboratory for syphilis testing were screened by the Guthrie test for hyperphenylalaninemia. Survey 3 Serum samples from 1548 mothers of children who were mentally retarded but did not have PKU were screened by the Guthrie test in various centres throughout the province to determine if mothers with undetected hyperphenylalaninemia were producing children with mental retardation due to intrauterine brain . Survey results Survey J From July 1965 through July 1975, 119 infants with persistent hyperphenylalaninemia were detected in Ontario (1:10 900 births): 71 were categorized as having classic PKU (1:18 500); 18, atypical PKU; and 30, persistent benign hyperphenylalaninemia. Four cases of classic PKU were missed by the testing program, three because the test was not done and one despite the test being done at 4 days of age (breast-fed female). Thirteen of the patients with atypical PKU were treated, four for 4 or more years, five for 2 to 3 years, two for 14 months, one for 7 months and one for 2 months. All but 1 of the 18 have normal intelligence quotients (IQs) (range, 95 to 116); the 1 has a borderline IQ (76), a first arch syndrome and some hearing loss (he was treated for 4 years). One of the patients with transient PKU had high serum phenylalanine values (up to 40 mg/dl) for 1 month. He was treated briefly and had a normal IQ and school performance at age 5 years. In some instances transient hyperphenylalaninemia was probably secondary to transient neonatal tyrosinemia (tyrosine concentration has been measured in all patients with positive Guthrie tests for only the last 3 years). In most the serum phenylalanine value was less than 10 mg/dl (only 12 values were over 10 mgldl) and the elevation lasted for less than 2 weeks. Tested parents of children with all categories of transient hyperphenylalaninemia had normal PIT ratios (less than 1.2).17 None of the children with persistent benign hyperphenylalaninemia were treated. All have normal IQs. All tested parents of this group of children had heterozygote PIT ratios (more than 1.2). The reported ratios of classic PKU to its variants are compared in Table III. The ratios in some other population groups have been summarized by Levy.6

Survey 2 Guthrie tests were positive in 9 of the 67 247 adults. Eight of the nine had serum phenylalanine values ranging from 6 to 14 mg/dl; repeat tests were negative in three, two died before repeat specimens could be obtained, two could not be traced and one (a man) had a repeat value of 9.5 mg/dl and a normal IQ. In the other person the original Guthrie test had estimated the serum phenylalanine value at 20 mg/dl; a second test, by the fluorometric technique, yielded a value of 22.2 mg/dl; the urine was positive for phenylpyruvic acid and his IQ was 100. In summary, this survey detected one individual with classic PKU and one with persistent benign hyperphenylalaninemia; both were men with normal intelligence. Survey 3 Of the 1548 mothers of mentally retarded children that were tested for hyperphenylalaninemia none had positive results. Discussiou Survey 1 The eventual classification of the hyperphenylalaninemias is likely to be complex. Most of the present classifications rely chiefly on serum phenylalanine values. Other factors in classification (see Table II) include dietary phenylalanine tolerance, heterozygous PIT ratios, results of phenylalanine loading tests (homozygote and heterozygote patterns), appearance of urine

metabolites and residual enzyme activity in the liver. Evidence of genetic difference is still only indirect. Most affected siblings have identical severity of hyperphenylalaninemia and central nervous system effects if untreated but enough exceptions have been described to confuse the situation further.464' Our ratio of classic PKU to atypical PKU and persistent benign hyperphenylalaninemia agrees with most ratios in reported North American series (Table III) but differs from those in other groups."7'50'51 It is important to distinguish atypical PKU from classic PKU because of the high tolerance to phenylalanine in the former and the consequent increased risk of an overly restrictive diet damaging the developing brain. Lines and Swanson52 found that the dietary phenylalanine requirement in benign persistent hyperphenylalaninemia is identical to that in classic PKU. We have not tested this finding. Our earlier contention that serum phenylalanine values of 5 to 15 mg/dl in patients with PKU undergoing dietary therapy were safe53 seems to be borne out by follow-up observations of IQs in untreated patients with various hyperphenylalaninemia traits. Detailed long-term studies, however, are most important to detect any evidence of minimal brain damage in patients with untreated benign hyperphenylalaninemia, untreated or briefly treated atypical PKU and "liberally treated" classic PKU. The serum phenylalanine values in benign hyperphenylalaninemia may gradually decrease as the patient grows older and adolescence approaches. Whether they increase again under the stress of pregnancy must be looked for carefully. The normal PIT ratios in the parents of the patients with transient disorders suggest delayed enzyme maturation in these infants rather than a genetically determined deficiency. Survey 2 Since the ratio of variants to classic PKU in North America is about 1:2 and the proportion of children with untreated PKU who have a normal IQ may be higher than previously estimated,' it has been suggested that in our present adult population there may be as many people with undetected hyperphenylalaninemia as with known PKU. It would be useful to detect persons with hyperphenylalaninemia (a) because of the potential risk to the unborn fetus of such women, (b) to determine the true proportion of persons with untreated PKU who have a

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normal IQ, (c) to find out what happens to benign hyperphenylalaninemia in adult life and (d) to determine if benign hyperphenylalaninemia is indeed harmless to the developing brain. Our small survey was more productive than others. Guthrie (personal communication cited by BickeP.) reviewed five such studies covering 392 800 people. Only three persons with elevated serum phenylalanine values were found; all had classic PKU and were retarded. Guthrie pointed out, however, that 25% of mentally retarded adults with PKU have serum phenylalanine values under 20 mg/dl, and he stated that all patients with values over 5 to 8 mg/dl should be treated indefinitely. However, persons with all types of hyperphenylalaninemia (PKU and its variants) have lower serum phenylalanine values as they grow older and the important values are probably those during the rapid and critical period of brain growth in the first 6 to 8 months of life. Survey 3 It is well documented that the offspring of women with untreated PKU are severely affected in utero."'55 Of one group of 123 offspring of 83 women with PKU, 98 had profound brain damage and 10 died.54 Of the 15 normal offspring most had mothers who were mildly affected or were undergoing dietary therapy. It is not known whether the stress of pregnancy increases the maternal serum phenylalanine concentration. The elevation of serum phenylalanine values in pregnant heterozygotes reported by Kang and Paine56 has not been substantiated by others.57 We have measured serum phenylalanine concentrations in eight pregnant women heterozygous for PKU and all have been normal. It has been shown in monkeys with hyperphenylalaninemia that the fetal serum phenylalanine values may be two or three times the maternal values.58 If women with PKU want to become pregnant a rigid low-phenylalanine diet should be instituted from conception. Successful treatment has been claimed.a4 To date our survey of a high-risk group of mothers has been unproductive.

et al: Causes for high phenylalanine with normal tyrosine. Am I Dis Child 117: 54, 1969 5. LEvY HL, SHIN VE, KAROLKEWJCZ V, et al: Persistent mild hyperphenylalaninemia in the untreated state. N Engi / Med 285: 424, 1971

6. LEVY H: Genetic screening, in Advances in Human Genetics, vol 4, HARRIS M, HIR5CHORN

K (eds), New York, Plenum Pr, 1973, p 28 7. SCRIVER CR, ROSENBERG LE:

Amino Acid

Metabolism and its Disorders, Philadelphia, Saunders, 1973, p 205 8. HsL4 DYY, 0'FLYNN ME: Hyperphenylalaninemia. Metabolism 16: 99, 1967

9. HsiA DYY: Phenylketonuria and its variants,

in Progress in Medical Genetics, STEINBERG AG, BEARN AG (eds), vol 7, New York, Grune, 1970, p 45

10. O'FLYNN ME, TILLMAN P, HsIA DYY: Hy-

perphenylalaninemia without phenylketonuria. Am J Dis Child 113: 22, 1967

11. AUERSACH VH, Di GEORGE AM, CARPENTER

GG: Phenylalaninemia, in Amino Acid Melabolism and Genetic Variations, NYHAN WL (ed), New York, McGraw, 1967, p 11 12. MABRY CC, NELSON TL, HORNER FA: Occult

phenylketonuria. Gun Pediatr (Phila) 1: 82, 1962

13. AUERBACH H, Di GEORGE AM, CAJiPENTER GG: Latent (delayed) PKU, in Amino Acid

Metabolism and Genetic Variations, op cit, p 38 14. CAsraLLs 5, LECAMERA RG, WEssEL M, et hyperphenylalaninemia. al: Transient I Pediatr 72: 530, 1968 15. GUTHRIE R, Susi A: A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediairics 32: 338, 1963 16. BREMER HJ, NEUMANN W: Tolerance of phenylalanine after intravenous administration in phenylketonurics, heterozygous carriers and normal adults. Nature 209: 1148, 1966 17. JACKSON SH, HANLEY WB, GEsto T, et al:

Detection of phenylketonuric heterozygotes. Clin Chem 17: 538, 1971 18. JusTicE P, O'FLYNN ME, HSJA DYY: Phenylalanine hydroxylase activity in hyperphenylalaninemia. Lancet 1: 928, 1967 19. BARTHOLOMEW K, LUTE P: Determination of phenylalanine-hydroxylase in phenylketonuria and hyperphenylalaninemia. Pediatr Res 8: 904, 1974 20. KAUFMAN 5, MAX EE, KANG ES: Phenylalanine hydroxylase activity in liver biopsies

from hyperphenylalaninemia heterozygotes deviation from proportionality with gene dosage. Pediatr Res 9: 632, 1975

21. Avaa. ME, CLOW CL, MENKES il-I, et al:

Transient tyrosinemia of the newborn: dietary and clinical aspects. Pediatrics 39: 378, 1967

22. HOLTZMAN

NA,

MEEK

AG,

MELLITS

ED:

Neonatal screening for phenylketonuria. IV. Factors influencing the occurrence of false positives. Am .1 Public Health 64: 755, 1974

23. PARTINGTON MW, VICKERY SK: Phenylketone-

mia in phenylketonuria. Neuropaediatrie 5: 125, 1974

24. YU

JS,

STUCKEY

SJ,

O'HALLORHAN

MT:

Atypical phenylketonuria: an approach to diagnosis and management. Arch Dis Child 45: 561, 1970 25. MENKES JH: A proposed classification for the hyperphenylalaninemias, in Proceedings of International Conference on Inborn Errors of Metabolism, Dubrovnik, Yugoslavia, US Dept

of

Health,

Education

and

Welfare,

children's bureau, 1967, p 23 26. KENNEDY JL JR, WERTELECKI W, GATES L, et al: The early treatment of phenylketonu-

References 1. JERVIS

GA:

Phenylpyruvic

oligophrcnia

(phenylketonuria). Res Pubi Assoc Res Nerv Ment Dis 33: 259, 1954

2. KNOX WE:

Incidence

and inheritance,

in

Phenylketonuria, LYMAN L (ed), Springfield IL, CC Thomas, 1963. p 11

3. MACCREADY RA, HUSSEY MG: Newborn phenylketonuria detection program in Massachusetts. Am J Public Health 54: 2075, 1964 4. BERMAN JL. CUNNINGHAM GC. DAY RW,

na. Am I Dis Child 113: 16, 1967 27. KUGEL RB, BARTRAN JB, BosT RB, Ct al: Committee on children with handicaps. Phenylketonuria and the phenylalaninemias of infancy. Pediatrics 49: 628, 1972 28. FRIMPTER GW: Aminoaciduria due to inherited disorders of metabolism (first of two parts). N Engi I Med 289: 835, 1973 29. READ KS, ALLEN RJ, HADDY TB: Phenylketonuria in newborns. Mich Med 68: 691, 1969 30. BERRY HK, SUTHERLAND BS, UMBARGER B: Diagnosis and treatment: interpretation of

512 CMA JOURNAL/SEPTEMBER 18, 1976/VOL. 115

results of blood screening studies for detection of phenylketonuria. Pediatrics 37: 102, 1966 31. KANG ES, KAUFMAN 5, GERALD PS: Clinical and biochemical observations of patients witji atypical phenylketonuria. Pediatrics 45: 83, 1970 32. WOOLF LI: Genetics of phenylalaninemia, in Phenylketonuria, BICKEL H, HUDSON FP, WOOLF LI (eds), Stuttgart, Georg Thieme Verlag, 1971, p 105 33. DYKEN P, CULLEY W: Another population of

phenylketonuria? Studies on atypical phenylketonurics. Dev Med Child Neurol 11: 718, 1969

34. B..Asiovscs ME, SCHAEFFLER GE, HACK 5: Phenylalaninemia: differential diagnosis. Arch Dis Child 49: 835, 1974 35. BICKEL H: Phenylalaninemia or classical phenylketonuria (PKU)? Neuropaediatrie 1: 379, 1970 36. GUTHRIE R: Personal communication, 1971

37. HUDSON FP: Hyperphenylalaninemia without phenylketonuria. Dev Med Child Neurol 9:

496, 1967 38. DONTANVILLE VK, CUNNINGHAM GC: Effect of feeding on screening for PKU in infants.

Pediatrics 51: 531, 1973 39. MCCAMAN MW, ROBINS

E:

Fluorimetric

method for the determination of phenylalanine in serum. I Lab Clin Med 59: 885, 1962 40. BROWN ES, WAISMAN HA: Mental retarda-

tion in four offspring of a hyperphenylalaninemic mother. Pediatrics 48: 401, 1971 41. BICKEL H: The treatment of phenylketonuria, in Phenylketonuria and Allied Metabolic Diseases, ANDERSON JA, SWAIMAN KF (eds), Washington, US Dept of Health, Education

and Welfare, children's bureau, 1967, pp 99-

115 42. MCBEAN MS: Hsai,9 1969

Personal

communication

to

43. GITZELMANN R: Der stand des neueborenen-

screening in der Schweiz. Bull Schweiz Akad Med Wiss 28: 294, 1972

44. KocH R, ACOSTA P, SHAW KNF, et al: Clinical aspects of PKU, in Phenylketonuria, op cit, p 21 45. BLAslcovlcs ME, SHAW KNF: Hyperphenylalaninemia: methods for differential diagnosis, in Phenylketonuria, op cit, p 98 46. KNOX WE: Phenylketonuria, in The Metabolic Basis of Inherited Disease, 3rd ed, STANBURY JB, WYNGAARDEN JB, FREDERICKSON DS (eds),

New York, McGraw, 1972, p 286

47. HsI. DYY, O'FLYNN ME, BERMAN JL: Atypical phenylketonuria with borderline or normal intelligence. Am I Dis Child 116: 143, 1968 48. ALLEN RJ, GIBSON RM: Phenylketonuria with normal intelligence. Am J Dis Child 102: 115, 1961 49. PIN EDA G: Variability in the manifestations

of phenylketonuria. I Pediatr 72: 528, 1968

50. COHEN BE, SZEINBERG A, BOIcHIs H, et al: Phenylketonuria in Yemenite Jews. Pediatrics 32: 1069, 1963 51. THALHAMMER 0, SciiEsaast V: Genetic difference hetween hyperphenylalaninemia and

phenylketonuria. Neuropaediatrie 3: 358, 1972

52. LINES DR, SWANSON M: Dietary requirement

of phenylalanine in infants with hyperphenyl-

alaninemia. Arch Dis Child 48: 648, 1973 53. HANLEY WB, LINsAo L, DAVIDSON W, et El: Malnutrition with early treatment of phenylketonuria. Pedlair Res 4: 318, 1970 54. HOWELL RR, STEVENSON RE: Maternal phenylketonuria. Soc BioL 18: 519, 1971 55. MACCREADY RA, LEvY HL: The problem of maternal phenylketonuria. Am I Obstet Gynecol 113: 121, 1972 56. KANG E, PAINE RS: Elevation of plasma

phenylalanine

levels during pregnancies of

women heterozygous for phenylketonuria. I

Pediatr 63: 283, 1963

57. BERRY HK, PONCET lB. SUTHERLAND BS, et

al: Serum amino acid concentrations during pregnancy of women heterozygous for phenylketonuria. Biol Neonate 26: 102, 1975 58. KERR GR, CISAMOVE AS, HARLOw HF, et al:

"Fetal PKU": the effect of maternal hyper-

phenylalaninemia during pregnancy in rhesus monkey. Pediatrics 42: 27, 1968

Ihe

Phenylketonuria variants in Ontario.

Phenylketonuria variants in Ontario ADVISORY COMMITTEE ON INBORN ERRORS OF METABOLISM * TO THE ONTARIO MINISTRY OF HEALTH Since mass screening of the...
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