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Phenylketonuria: phenylpyruvic aciduria
COMMENTS CURRENT
ON LITERATURE
Pheny l keton u ria : pheny lpyru vic aciclu ria
the disease in this way. 2' 5, 6 In his excellent reviews dealing with phenylketonuria and other inborn errors of metabolism, I-Isias, 4 has summarized the genetic, clinical, and prophylactic features of the disease. In a recent interview Hsia 7 stated that "If every baby born in the United States from now on were given this simple chemical test, several thousand could be saved from mental retardation in each generation . . . . But unless the condition is caught in the first few weeks of life and controlled by diet, the child's brain development is impaired. ''7 While these patients with phenylketonuria have brain damage resulting in one of the severest grades of mental retardation (imbecile level), they are unusually attractive physically, as a rule. Unlike other mentally defective persons they show only slight reduction in stature and head size, as compared with the normal average for the same age and sex. A few of these patients have a tendency to develop dermatitis or eczema which in some recorded instances has been the presenting symptom that led to further investigation, with the definitive diagnosis of phenylketonuria. On neurological examination patients with phenylketonuria show no paralysis and no changes in muscle tone. Often, however, there is marked accentuation of both superficial and deep tendon reflexes. Most of the patients without treatment show eventually a low level of mental capacity with an I.Q. of 30 or less. ~ Re-
PHENYLKETONURIA is an inherited condition characterized by mental retardation and the presence of phenylpyruvic acid in the urine. More than 400 well-documented cases have been reported from all parts of the world since the first description of the disease in 1934 by the Norwegian biochemist, F611ing? While the most striking feature of phenylketonuria is mental deficiency, it is now generally agreed that the primary lesion is an inborn error of metabolism. Patients with phenylketonuria are not able to metabolize phenylalanine adequately, by the direct pathway to tyrosine, because of a deficiency of the enzyme, phenylalanine hydroxylase. As a result, phenylalinine accumulates in the blood and the cerebrospinal fluid, and various phenylalanine metabolites, including phenylketones, appear in the urine. One of these metabolites is phenylpyruvic acid which gives a characteristic green color with ferric chloride, a test now recognized as a simple means of identifying the disease.Z, a Within the past few years it has become apparent that the early treatment of phenylketonnria by means of a low phenylalanine diet will prevent the development of brain damage. Emphasis is placed on early diagnosis and early treatment, s' 4 Diagnosis can seldom be made on clinical grounds alone. 2 Urine testing for phenylketonuria is simple, inexpensive, and reliable after the first month of life. a, 4 It has been suggested that all infants be screened for 294
Volume 59
Number 2
cently a few borderline cases have been reported with definite diagnosis of phenylketonuria, but in which the intelligence quotient was near the normal average. These atypical cases, however, represent a very small percentage of the total cases of phenylketonuria. That there is considerable variability in the clinical manifestations of phenylketonuria was recognized and stressed in early case reports. < ~ In an extensive study by Paine 8 in 1957 this range of variability is emphasized, as well as the question of deterioration of intelligence and performance with age. One hundred and six cases were surveyed in 11 institutions in the New England area and in eastern Canada. Both eczema and seizures were proportionately more frequent in severely retarded patients with phenylketonuria than in those with lesser degrees of intellectual defect. Electroencephalographic studies showed abnormal tracings in 79 per cent of those examined in this respect, and such studies were considered important in planning therapy for these patients, even in the absence of seizures. While the majority of these children did have the characteristic fair skin with blue eyes and blond hair, in some there was definite darkening of skin and hair with age, so that these traits have questionable value in diagnosis or in treatment evaluation. Neurological manifestations encountered in this study included unusual hand posturing, tremor, hyperreflexia, agitated behavior, clonus, and spasticity, all of which varied considerably from patient to patient, and at different times in the same patient. In those children followed over a period of time, deterioration with age was apparent. Recently Partington ~ reviewed the earliest possible clinical history of 36 patients with phenylketonuria, concluding that in at least one half this number suggestive symptoms began in the first few weeks of life. Among these early symptoms vomiting, irritability, infantile eczema, and a peculiar characteristic odor were prominent. Some of the patients in this group had all the early symptoms. Three of the 36 infants had pyloric stenosis. It is suggested
C o m m e n t s on current literature
29 5
that the "vomiting and irritability in early life may be due to a 'toxic' effect of phenylalanine or its derivatives on the brain. '''~ Hsia and his associates 2 estimate that phenylketonuria accounts for about 1 per cent of all mentally defective patients in institutions. The condition is thought to occur once in every 40,000 births in the United States and is transmitted by inheritance by a relatively rare recessive gene. In any given family with one child affected, the statistical chance of the condition being present in a subsequent child is 1 in 4. In 1956, Hsia and his co-workers 9 described the detection of heterozygous carriers of this recessive gene for phenylketonuria by means of the phenylalanine tolerance tests in which 0.1 Gm. per kilogram of body weight of L-phenylalanine was administered by oral route to normal control subjects and to parents of children with known phenylketonuria. One, two, and four hours after the initial dose, blood samples were taken for the determination of plasma phenylalanine levels. Following this dose load, parents of patients with phenylketonuria showed definite increase in plasma phenylalanine as compared with the controls. Subsequently, similar determinations were carried out in 200 relatives of children with phenylketonuria in 40 affected families. Carriers of the recessive trait can be detected readily by this means. All the studies indicated transmission by inheritance according to an autosomal recessive pattern. The pathogenetic and biochemical basis for phenylketonuria and the nature of the enzymatic defect are being investigated. Phenylalanine is converted to tyrosine by the enzyme system, phenylalanine hydroxylase. Mitoma and his fellow workers 1~ were able to show that 2 protein fractions are involved in this reaction: (1) a labile fraction I, which is present only in the liver, and (2) a more stable fraction II, found in the kidney and the heart, as well as in the liver. In phenylketonuria fraction I I is present in normal amounts; the disease condition occurs because of a deficiency of fraction I of the enzyme system. Excessive
296
Comments
on c u r r e n t literature
accumulation of L-phenylalanine in the blood and the spinal fluid brings about 3 basic effects. 2' 9 The excessive phenyalanine is converted by its transaminase to phenyIpyruvic acid which is found in the urine together with some of its breakdown products, including phenylketones. The presence of phenylalanine in excessive amounts inhibits the normal pathways of tyrosine metabolism. In consequence, melanin production is decreased, which is responsible for the fair skin and hair of such children. Disturbance in epinephrine production is also a feature of the disease, since these patients have relatively low .blood levels of epinephrine. The excessive phenylalanine or some of its products occurring in the blood and the spinal fluid appear to be the factor or factors in central nervous system damage. Because of the severe mental retardation resulting from phenylketonuria, surveys and screening programs are being conducted in a number of medical centers in Great Britain and Europe, and in Canada and the United States2, 6, 11 Recent improvements in testing procedures include the use of ferric chloride impregnated paper strips (Phenistix~), the Schieffelin test kit for examination of wet diapers (10 per cent ferric chloride), or the use of dinitrophenylhydrazine test solution2, 1~ Direct blood tests by means of paper chromatography and by an enzymatic spectrophotometric method la are possible. Young infants can be treated satisfactorily by the use of a special diet low in phenylalanine content such as the following: a low phenylalanine protein hydrolysate, 1 per cent protein fruits and vegetables, glutenfree bread, sugar, b u t t e r , or lipomal, and vitamin and mineral supplements. This diet appears to be adequate for normal development if started early in life; however, considerable adjustments must be made for older children, particularly after the age of 13 years, z, 14 In this connection recent reports by Moncrieff and Wilkinson 15 and Coates ~6
~Amcs Company, Inc., Elkhmt, Ind.
August 1961
are of special interest. These authors discuss many problems associated with the detection and treatment of phenylketonuria. With respect to detection they caution that proper use of the urine and blood tests is important, since false positives are possible. A significant observation is that these levels m a y vary when infection and fever are present in the young child. In the actively developing young infant the diet m a y have to be more generous in phenylalanine even to the extent of exceeding the normal blood level if the child is to survive and thrive. The normal infant doubles in weight in 5 months and at this age relatively small deficiencies in essential amino acids and vitamins may produce defects in growth. Some infants are more difficult to handle than others insofar as dietetic control is concerned. Such control can be based only on closely followed serial estimations of phenylalanine levels in the blood. The available preparations of casein hydrolysate have had the phenylalanine removed as completely as possible; tyrosine and tryptophan have been removed at the same time and must be repIaced. T h e authors at present are reviewing the situation with reference to vitamin .B supplementation. In older children the daily allowance of milk may be increased, with possible consideration of increased tyrosine and tryptophan. T h a t older infants and children can tolerate increasing amounts of phenylalanine in the diet has been recognized for some years. The possible mechanism of increased tolerance is discussed. In a separate publication Coates! ~ describes in detail the dietary management of 35 cases of phenylketonuria, including 6 in which treatment was gradually reduced and finally terminated. This author points out, however, that such dietary relaxation requires individual evaluation, and that all information with regard to its effect on mental capacity is as yet strictly preliminary. These authors 15' 16 emphasize the importance of further investigation especially with reference to the experimental studies in laboratory animals currently in progress. Workers in a number of laboratories are
Volume 59
Number 2
investigating the effects of o v e r l o a d i n g p h e n y l a l a n i n e a n d tyrosine in the diet of animals with a view to a better u n d e r s t a n d ing of the m e t a b o l i c processes a n d the enzyme systems involved. W a i s m a n a n d his colleagues ~7 have succeeded in i n d u c i n g a -condition in y o u n g monkeys w h i c h is similar to t h a t seen in children with phenylketonuria. I n 2 m o n k e y s inferior intellectual developm e n t resulted from consistent overload a n d a m a j o r convulsive disorder o c c u r r e d in b o t h animals. E x p e r i m e n t a l l y i n d u c e d phenylk e t o n u r i a has been r e p o r t e d r e c e n t l y in investigations dealing with weanling rats. H u a n g , Hsia, a n d their co-workers *s h a d shown previously t h a t certain enzyme systems in the n e w b o r n r a t kidney are i m m a ture, such as 5 - h y d r o x y t r y p t o p h a n d e c a r boxylase, a n d t h a t m a t u r i t y of these enzyme systems g r a d u a l l y occurs during the first 30 days of life to the a d u l t r a t level. F r o m a study of i n d u c e d p h e n y l k e t o n u r i a in the young r a t these investigators suggest a possible close relationship between the phenylalanine complexes a n d the enzyme system involving 5 - h y d r o x y t r y p t o p h a n d e c a r b o x y lase. T h e y offer the tentative suggestion that "excessive amounts of p h e n y l a l a n i n e in the p h e n y l k e t o n u r i c child would f u r t h e r inhibit an a l r e a d y i m m a t u r e enzyme system, and this in t u r n will result in a decrease of 5 - h y d r o x y t r y p t a m i n e which is essential to the developing brain, ms Investigations currently in progress in this field dealing with i n d u c e d m e t a b o l i c disorders in animals will be of considerable interest. T h e concept of " i n b o r n errors of m e t a b o lism," first suggested b y Sir A r c h i b a l d G a r r o d 19 in 1908, has assumed a new significance within recent years as i n f o r m a t i o n from various sources from genetics a n d biochemistry, a n d f r o m clinical a n d experim e n t a l observations, is correlated. As H s i a points out, the past few years have witnessed " u n p r e c e d e n t e d progress" in these fields of knowledge which "has p e r m i t t e d for the first time a logical a p p r o a c h to the various inborn errors of m e t a b o l i s m in man. ''2
RUSSELL J. BLATTNER~ M.D.
Comments on current literature
297
REFERENCES
1. FSlling, A.: Ueber Ausscheidung von Phenylo brenztraubens~iure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillit~it, Ztschr. physiol. Chem. 227: I69, 1934. 2. J-Isia, David Y.-Y.: Inborn Errors of Metabolism, Chicago, 1959, The Year Book Publishers, Inc. Recent Developments in Inborn Errors of Metabolism, Am. J. Pub. Health 50: 1653, 1960. 3. Allen, R. J.: The Detection and Diagnosis of Phenylketonuria, Am. J. Pub. Health 50: 1662, 1960. 4. Knox, W. E., and Hsia, David Y.-Y.: Pathogenetic Problems in Phenylketonuria, Am. J. Med. 22: 687, 1957. Knox, W. E.: An Evaluation of the Treatment of Phenylketonuria With Diets Low in Phenylalanine, Pediatrics 26: 1, 1960. 5. Centerwall, W. R., Chinnock, R. F., and Pusavat, A.: Phenytketonuria: Screening Programs and Testing Method, Am. J. Pub. Health 50: 1667, 1960. 6. Partington, M. W.: The Early Symptoms of Phenylketonuria, Pediatrics 27: 465, 1961. Observations on Phenylketonuria in Ontario, Canad. M. A. J. 84: 985, 1961. 7. Hsia, David Y.-Y.: Interview: Article by L. Pompain: Far-Reaching Fight Against Mental Retardation, A. M. A. Today's Health, May, 1961, p. 46. 8. Paine, R. S,: The Variability in Manifestations of Untreated Patients With Phenylketonuria (Phenylpyruvie Acidnria), Pediatrics 20: 290, 1957. 9. Hsia, David Y.-Y., Driscoll, K. W., Troll, W., and Knox, W. E.: Detection of the Heterozygous Carrier for Phenylketonuria by Phenytalanine Tolerance Tests, Nature 178: 1239, 1956. 10. Mitoma, C., Anld, R. M., and Udenfriend, S.: On The Nature of the Enzymatic Defect in Phenylpyruvic Oligophrenia, Proc. Soc. Exper. Biol. & Med. 94: 634, 1957. 1l. Boyd, Mary M. M.: Phenylketonuria: City of Birmingham Screening Survey, Brit. M. J. 1: 771, 1961. 12. Wright, S. W., and Tarjan, G.: Phenylketonuria, A. M. A. J. Dis. Child. 93" 405, 1957. 13. La Du, B. N., and Michael, P. J.: An Enzymatic Spectrophotometric Method for the Determination of Phenylalanine in the Blood, J. Lab. & Ciin. Med. 55: 491, 1960. 14. Woolf, L. I., Griffiths, R., and Moncrieff, A.: A Treatment of Phenylketonuria With a Diet Low in Phenylalanine, Brit. M. J. 1: 57, 1955. Woolf, L. I., Griffiths, R., Moncrieff, A . , Coates, S., and Dillistone, F.: The Dietary !~ Treatment of Phenylketonuria, Arch. Dis. Childhood 33: 31, 1958. 15. Moncrieff, A., and Wilkinson, R. H.: Further Experiences in the Treatment of Phenytketonuria, Brit. M. J. l: 763, 1961.
298
Comments
on c u r r e n t l i t e r a t u r e
16. Coates, S.: Results of Treatment in Phenylketonuria, Brit. M. J. 1: 767, 1961. 17. Waisman, H. A., Wang, H. L., Harlow, H. F., and Sponholz, R. R.: Experimental Phenylketonuria in the Monkey, Proe. Soc. Exper. Biol. & Med. 101: 864, 1959. Waisman, H. A., and Wang, H. L.: Attempts to Influence Phenylalanine Plasma Levels by Oral Feedings, Abst. No. 93, Am. Pediat. Sot., Sixty-ninth Annual Meeting, May 6 to 8, 1959, Buck Hill Falls, Pa. Waisman, H. A., and Harlow, H. F.: Phenylketonuria in Infant Monkeys, Abst. No. 26, Am. Pediat. Soc. Seventieth Annual Meeting, May 5 to 6, 1960, Swampscott, Mass.
August 1961
18. Huang, I., Tannenbaum, S., Blume, L., and Hsia, David Y.-Y.: Metabolism of 5-Hydroxyindole Compounds in Experimentaily Produced Phenylketonuric Rats, Proc. Soc. Exper. Biol. & Med. 106: 533, 1961. 19. Garrod, Sir Archibald E.: Inborn Errors of Metabolism, The Croonian Lectures, Royal College of Physicians, June, 1908, Lancet 2: 1, 73, 142, 214, 1908; Published London, 1909, Henry Frowde, Ltd.; ed. 2 London, 1923, Henry Frowde, Hodder and Stoughton, Ltd.
ON LITERATURE
Pheny l keton u ria : pheny lpyru vic aciclu ria
the disease in this way. 2' 5, 6 In his excellent reviews dealing with phenylketonuria and other inborn errors of metabolism, I-Isias, 4 has summarized the genetic, clinical, and prophylactic features of the disease. In a recent interview Hsia 7 stated that "If every baby born in the United States from now on were given this simple chemical test, several thousand could be saved from mental retardation in each generation . . . . But unless the condition is caught in the first few weeks of life and controlled by diet, the child's brain development is impaired. ''7 While these patients with phenylketonuria have brain damage resulting in one of the severest grades of mental retardation (imbecile level), they are unusually attractive physically, as a rule. Unlike other mentally defective persons they show only slight reduction in stature and head size, as compared with the normal average for the same age and sex. A few of these patients have a tendency to develop dermatitis or eczema which in some recorded instances has been the presenting symptom that led to further investigation, with the definitive diagnosis of phenylketonuria. On neurological examination patients with phenylketonuria show no paralysis and no changes in muscle tone. Often, however, there is marked accentuation of both superficial and deep tendon reflexes. Most of the patients without treatment show eventually a low level of mental capacity with an I.Q. of 30 or less. ~ Re-
PHENYLKETONURIA is an inherited condition characterized by mental retardation and the presence of phenylpyruvic acid in the urine. More than 400 well-documented cases have been reported from all parts of the world since the first description of the disease in 1934 by the Norwegian biochemist, F611ing? While the most striking feature of phenylketonuria is mental deficiency, it is now generally agreed that the primary lesion is an inborn error of metabolism. Patients with phenylketonuria are not able to metabolize phenylalanine adequately, by the direct pathway to tyrosine, because of a deficiency of the enzyme, phenylalanine hydroxylase. As a result, phenylalinine accumulates in the blood and the cerebrospinal fluid, and various phenylalanine metabolites, including phenylketones, appear in the urine. One of these metabolites is phenylpyruvic acid which gives a characteristic green color with ferric chloride, a test now recognized as a simple means of identifying the disease.Z, a Within the past few years it has become apparent that the early treatment of phenylketonnria by means of a low phenylalanine diet will prevent the development of brain damage. Emphasis is placed on early diagnosis and early treatment, s' 4 Diagnosis can seldom be made on clinical grounds alone. 2 Urine testing for phenylketonuria is simple, inexpensive, and reliable after the first month of life. a, 4 It has been suggested that all infants be screened for 294
Volume 59
Number 2
cently a few borderline cases have been reported with definite diagnosis of phenylketonuria, but in which the intelligence quotient was near the normal average. These atypical cases, however, represent a very small percentage of the total cases of phenylketonuria. That there is considerable variability in the clinical manifestations of phenylketonuria was recognized and stressed in early case reports. < ~ In an extensive study by Paine 8 in 1957 this range of variability is emphasized, as well as the question of deterioration of intelligence and performance with age. One hundred and six cases were surveyed in 11 institutions in the New England area and in eastern Canada. Both eczema and seizures were proportionately more frequent in severely retarded patients with phenylketonuria than in those with lesser degrees of intellectual defect. Electroencephalographic studies showed abnormal tracings in 79 per cent of those examined in this respect, and such studies were considered important in planning therapy for these patients, even in the absence of seizures. While the majority of these children did have the characteristic fair skin with blue eyes and blond hair, in some there was definite darkening of skin and hair with age, so that these traits have questionable value in diagnosis or in treatment evaluation. Neurological manifestations encountered in this study included unusual hand posturing, tremor, hyperreflexia, agitated behavior, clonus, and spasticity, all of which varied considerably from patient to patient, and at different times in the same patient. In those children followed over a period of time, deterioration with age was apparent. Recently Partington ~ reviewed the earliest possible clinical history of 36 patients with phenylketonuria, concluding that in at least one half this number suggestive symptoms began in the first few weeks of life. Among these early symptoms vomiting, irritability, infantile eczema, and a peculiar characteristic odor were prominent. Some of the patients in this group had all the early symptoms. Three of the 36 infants had pyloric stenosis. It is suggested
C o m m e n t s on current literature
29 5
that the "vomiting and irritability in early life may be due to a 'toxic' effect of phenylalanine or its derivatives on the brain. '''~ Hsia and his associates 2 estimate that phenylketonuria accounts for about 1 per cent of all mentally defective patients in institutions. The condition is thought to occur once in every 40,000 births in the United States and is transmitted by inheritance by a relatively rare recessive gene. In any given family with one child affected, the statistical chance of the condition being present in a subsequent child is 1 in 4. In 1956, Hsia and his co-workers 9 described the detection of heterozygous carriers of this recessive gene for phenylketonuria by means of the phenylalanine tolerance tests in which 0.1 Gm. per kilogram of body weight of L-phenylalanine was administered by oral route to normal control subjects and to parents of children with known phenylketonuria. One, two, and four hours after the initial dose, blood samples were taken for the determination of plasma phenylalanine levels. Following this dose load, parents of patients with phenylketonuria showed definite increase in plasma phenylalanine as compared with the controls. Subsequently, similar determinations were carried out in 200 relatives of children with phenylketonuria in 40 affected families. Carriers of the recessive trait can be detected readily by this means. All the studies indicated transmission by inheritance according to an autosomal recessive pattern. The pathogenetic and biochemical basis for phenylketonuria and the nature of the enzymatic defect are being investigated. Phenylalanine is converted to tyrosine by the enzyme system, phenylalanine hydroxylase. Mitoma and his fellow workers 1~ were able to show that 2 protein fractions are involved in this reaction: (1) a labile fraction I, which is present only in the liver, and (2) a more stable fraction II, found in the kidney and the heart, as well as in the liver. In phenylketonuria fraction I I is present in normal amounts; the disease condition occurs because of a deficiency of fraction I of the enzyme system. Excessive
296
Comments
on c u r r e n t literature
accumulation of L-phenylalanine in the blood and the spinal fluid brings about 3 basic effects. 2' 9 The excessive phenyalanine is converted by its transaminase to phenyIpyruvic acid which is found in the urine together with some of its breakdown products, including phenylketones. The presence of phenylalanine in excessive amounts inhibits the normal pathways of tyrosine metabolism. In consequence, melanin production is decreased, which is responsible for the fair skin and hair of such children. Disturbance in epinephrine production is also a feature of the disease, since these patients have relatively low .blood levels of epinephrine. The excessive phenylalanine or some of its products occurring in the blood and the spinal fluid appear to be the factor or factors in central nervous system damage. Because of the severe mental retardation resulting from phenylketonuria, surveys and screening programs are being conducted in a number of medical centers in Great Britain and Europe, and in Canada and the United States2, 6, 11 Recent improvements in testing procedures include the use of ferric chloride impregnated paper strips (Phenistix~), the Schieffelin test kit for examination of wet diapers (10 per cent ferric chloride), or the use of dinitrophenylhydrazine test solution2, 1~ Direct blood tests by means of paper chromatography and by an enzymatic spectrophotometric method la are possible. Young infants can be treated satisfactorily by the use of a special diet low in phenylalanine content such as the following: a low phenylalanine protein hydrolysate, 1 per cent protein fruits and vegetables, glutenfree bread, sugar, b u t t e r , or lipomal, and vitamin and mineral supplements. This diet appears to be adequate for normal development if started early in life; however, considerable adjustments must be made for older children, particularly after the age of 13 years, z, 14 In this connection recent reports by Moncrieff and Wilkinson 15 and Coates ~6
~Amcs Company, Inc., Elkhmt, Ind.
August 1961
are of special interest. These authors discuss many problems associated with the detection and treatment of phenylketonuria. With respect to detection they caution that proper use of the urine and blood tests is important, since false positives are possible. A significant observation is that these levels m a y vary when infection and fever are present in the young child. In the actively developing young infant the diet m a y have to be more generous in phenylalanine even to the extent of exceeding the normal blood level if the child is to survive and thrive. The normal infant doubles in weight in 5 months and at this age relatively small deficiencies in essential amino acids and vitamins may produce defects in growth. Some infants are more difficult to handle than others insofar as dietetic control is concerned. Such control can be based only on closely followed serial estimations of phenylalanine levels in the blood. The available preparations of casein hydrolysate have had the phenylalanine removed as completely as possible; tyrosine and tryptophan have been removed at the same time and must be repIaced. T h e authors at present are reviewing the situation with reference to vitamin .B supplementation. In older children the daily allowance of milk may be increased, with possible consideration of increased tyrosine and tryptophan. T h a t older infants and children can tolerate increasing amounts of phenylalanine in the diet has been recognized for some years. The possible mechanism of increased tolerance is discussed. In a separate publication Coates! ~ describes in detail the dietary management of 35 cases of phenylketonuria, including 6 in which treatment was gradually reduced and finally terminated. This author points out, however, that such dietary relaxation requires individual evaluation, and that all information with regard to its effect on mental capacity is as yet strictly preliminary. These authors 15' 16 emphasize the importance of further investigation especially with reference to the experimental studies in laboratory animals currently in progress. Workers in a number of laboratories are
Volume 59
Number 2
investigating the effects of o v e r l o a d i n g p h e n y l a l a n i n e a n d tyrosine in the diet of animals with a view to a better u n d e r s t a n d ing of the m e t a b o l i c processes a n d the enzyme systems involved. W a i s m a n a n d his colleagues ~7 have succeeded in i n d u c i n g a -condition in y o u n g monkeys w h i c h is similar to t h a t seen in children with phenylketonuria. I n 2 m o n k e y s inferior intellectual developm e n t resulted from consistent overload a n d a m a j o r convulsive disorder o c c u r r e d in b o t h animals. E x p e r i m e n t a l l y i n d u c e d phenylk e t o n u r i a has been r e p o r t e d r e c e n t l y in investigations dealing with weanling rats. H u a n g , Hsia, a n d their co-workers *s h a d shown previously t h a t certain enzyme systems in the n e w b o r n r a t kidney are i m m a ture, such as 5 - h y d r o x y t r y p t o p h a n d e c a r boxylase, a n d t h a t m a t u r i t y of these enzyme systems g r a d u a l l y occurs during the first 30 days of life to the a d u l t r a t level. F r o m a study of i n d u c e d p h e n y l k e t o n u r i a in the young r a t these investigators suggest a possible close relationship between the phenylalanine complexes a n d the enzyme system involving 5 - h y d r o x y t r y p t o p h a n d e c a r b o x y lase. T h e y offer the tentative suggestion that "excessive amounts of p h e n y l a l a n i n e in the p h e n y l k e t o n u r i c child would f u r t h e r inhibit an a l r e a d y i m m a t u r e enzyme system, and this in t u r n will result in a decrease of 5 - h y d r o x y t r y p t a m i n e which is essential to the developing brain, ms Investigations currently in progress in this field dealing with i n d u c e d m e t a b o l i c disorders in animals will be of considerable interest. T h e concept of " i n b o r n errors of m e t a b o lism," first suggested b y Sir A r c h i b a l d G a r r o d 19 in 1908, has assumed a new significance within recent years as i n f o r m a t i o n from various sources from genetics a n d biochemistry, a n d f r o m clinical a n d experim e n t a l observations, is correlated. As H s i a points out, the past few years have witnessed " u n p r e c e d e n t e d progress" in these fields of knowledge which "has p e r m i t t e d for the first time a logical a p p r o a c h to the various inborn errors of m e t a b o l i s m in man. ''2
RUSSELL J. BLATTNER~ M.D.
Comments on current literature
297
REFERENCES
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16. Coates, S.: Results of Treatment in Phenylketonuria, Brit. M. J. 1: 767, 1961. 17. Waisman, H. A., Wang, H. L., Harlow, H. F., and Sponholz, R. R.: Experimental Phenylketonuria in the Monkey, Proe. Soc. Exper. Biol. & Med. 101: 864, 1959. Waisman, H. A., and Wang, H. L.: Attempts to Influence Phenylalanine Plasma Levels by Oral Feedings, Abst. No. 93, Am. Pediat. Sot., Sixty-ninth Annual Meeting, May 6 to 8, 1959, Buck Hill Falls, Pa. Waisman, H. A., and Harlow, H. F.: Phenylketonuria in Infant Monkeys, Abst. No. 26, Am. Pediat. Soc. Seventieth Annual Meeting, May 5 to 6, 1960, Swampscott, Mass.
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18. Huang, I., Tannenbaum, S., Blume, L., and Hsia, David Y.-Y.: Metabolism of 5-Hydroxyindole Compounds in Experimentaily Produced Phenylketonuric Rats, Proc. Soc. Exper. Biol. & Med. 106: 533, 1961. 19. Garrod, Sir Archibald E.: Inborn Errors of Metabolism, The Croonian Lectures, Royal College of Physicians, June, 1908, Lancet 2: 1, 73, 142, 214, 1908; Published London, 1909, Henry Frowde, Ltd.; ed. 2 London, 1923, Henry Frowde, Hodder and Stoughton, Ltd.