FRANCOIS R, QUINCY C, RIEDWEG M, et al: Encephalopathie congenitale familiale associeea une anomalie du metabolisme de la tyrosine. Pe'- diatrie 17: ...
Tyrosinosis: Witold A.
Zaleski,
a new
m.d., d.p.m.,
Saskatoon, Sask.
f.r.c.p.[c] and Alan Hill, ph.d.,
Summary: Abnormalities of tyrosine metabolism are discussed under four headings: (1) accumulation of tyrosine and its metabolites secondary to severe liver damage, vitamin C deficiency, etc; (2) transient neonatal tyrosinemia; (3) hereditary tyrosinosis with hepatorenal dysfunction where elevation of tyrosine and methionine levels in the plasma may be a secondary manifestation of an unknown disease process; and (4) "essential tyrosinemia" or tyrosinosis without hepatorenal dysfunction which may represent a primary fault in the metabolism of tyrosine. A new case of tyrosinosis without hepatorenal dysfunction in a 13-year-oId mentally retarded girl is reported. Clinical findings, laboratory investigations and results of dietary management and normalization of the plasma tyrosine level and of urinary metabolites are presented and compared with the features of three similar cases in the literature. It is suggested that these cases represent "essential tyrosinemia" where there is a primary genetic defect in tyrosine metabolism.
From the Alvin Buckwold Centre, Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan w. a.
zaleski,
Director,
Alvin Buckwold Centre and Associate Professor of Pediatrics, University of Saskatchewan a.
hill,
Biochemist,
Alvin Buckwold Centre This study was supported by Public Health Research Grant (Project #607-7-143) of the National Health Grants Program
variant
(Canada) Reprint requests to: Dr. W. A. Zaleski, Alvin Buckwold Centre, University Hospital, Saskatoon, Sask.
Since the first report of abnormal
tyrosine metabolism by Medes in 19321 elevated blood tyrosine has been reported in several different biochemical and phenotypical varia¬ tions. Clinically, disorders of tyrosine metabolism range from the benign condition of neonatal tyrosinemia to a rapidly fatal hereditary tyrosi¬ nosis. The common biochemical de¬ nominator is increased- plasma ty¬ rosine level and tyrosyluria (pres¬ ence of tyrosine and its derivatives in urine). The dysfunction in tyrosine de¬ gradation may be subdivided into four etiological groups: Group I: Tyrosine elevation sec¬ ondary to severe liver damage, pernicious anemia or vitamin C deficiency. Levine and Conn2 have recently provided consider¬ able evidence for defective me¬ tabolism of tyrosine in a variety of diseases of the liver accom¬ panied by cirrhosis. Group II: Immaturity of the en¬ zyme system, parahydroxyphenylpyruvic acid (PHPPA) oxidase, as in neonatal tyrosinemia (be¬ nign hypertyrosinemia). This is a well-known condition of tran¬ sient elevation of serum tyrosine, together with tyrosyluria, occur¬ ring occasionally in premature and in some term infants fed a high protein diet.3"5 Group III: Disorders described in the literature as tyrosinosis, here¬ ditary tyrosinemia and inborn hepatorenal dysfunction,6"10 in which tyrosinemia and tyrosyluria are associated with liver or kid¬ ney damage. Methioninemia, aminoaciduria and glycosuria have been almost constant fea¬ tures of this form of tyrosinosis in the untreated state. In spite of early conjecture it has not been established that tyrosinosis associated with hepa¬ torenal disease is a primary de¬ fect of tyrosine metabolism and not a consequence of liver dis¬ ease. It is probable that decreased
ability to metabolize tyrosine and methionine is an independent secondary manifestation of a dis¬ ease process as yet unidentified. In its most frequently de¬ scribed form hereditary tyrosi¬
nosis presents as an acute pro¬ gressive illness starting in the neonatal period. There are signs of hepatic failure, renal tubular dysfunction and vitamin D-resistant rickets, and in 90% of cases death occurs in infancy. Children surviving the first year of life show severe psychomotor retardation and most of "them die of hepatic and renal failure in the first decade. A large group of such cases, located in the Chicoutimi region of Quebec, was described in this Journal in 1967.11 Group IV: More recently identi¬ fied cases of tyrosinemia and tyrosyluria without hepatorenal disease. These cases may actually be examples of "essential tyrosi¬ nemia" a primary genetic de¬ fect in tyrosine metabolism. For lack of a better name this condi¬ tion is usually referred to as "tyrosinosis without hepatorenal .
disease".
In the three cases so far re¬ ported this form of tyrosinosis is associated with mental retarda¬ tion.12"15 It runs a non-progressive course and, in spite of high plasma tyrosine levels and tyro¬ syluria, there is no elevation of the methionine level and both liver and kidney function remain
normal. In this paper the clinical and bio¬ chemical findings and details of dietary therapy in a teenage girl whose disorder was diagnosed as tyrosinosis without hepatorenal dis¬ ease are presented. Routine screen¬ ing for inborn errors of metabolism of all the institutionalized retarded patients in Saskatchewan, conducted by our Centre, led to discovery of this case. The nitrosonaphthol test16 was strongly positive and aminoacid chromatography revealed a large amount of tyrosine in blood and urine. The biochemical parameters have been monitored for over three years, and a long period of normalization of plasma tyrosine has been achieved using a phenylalanine-tyrosine-restricted diet. CMA. JOURNAL/FEBRUARY 17, 1973/VOL. 108 477
New
Case report
Synac hene
DePao * Synhec sce to animal ACTH
*Amorephioigical of firp
srds
SYNACTHEN DEPOT
(Cosyntropin Zinc Hydroxide Suspension) SYNACTHEN DEPOT is a long-acting synthetic alpha 1-24-corticotropin that exhibits the same activity as natural ACTH with regard to its biological activity, except that it displays less antigenicity.
Indications and Clinical Uses SYNACTHEN DEPOT is indicated in all cases where prolonged stimulation of the adrenal cortex is sought, as in Allergic Diseases (e.g., bronchial asthma), Collagen Diseases (e.g., rheumatoid arthritis) or Dermatologic Diseases (e.g., atopic dermatitis). For a complete list of approved indications, please refer to the Product Monograph.
Contraindications
Absolute Contraindications: Tuberculosis (active, healed or questionably healed); ocular herpes simplex; acute psychosis. Relative Contraindications: Cushing's disease; congestive heart failure; diverticulitis; recent intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; thromboembolic tendencies; acute or chronic infections, especially varicella or vaccinia; exanthematous and fungal diseases. Pregnancy, particularly during the first trimester. If SYNACTHEN DEPOT is used in any of the above conditions, the risks should be weighed against the possible benefits.
Warnings
SYNACTHEN DEPOT must not be given intravenously.
Precautions
Although SYNACTHEN DEPOT does not contain animal protein, nor the most antigenic part of the natural ACTH molecule, allergic reactions of both dermal and systemic types remain a remote possibility. Should such reactions occur, treatment must be stopped. The blood press4re and weight should be carefully observed. Urinalysis should be done at intervals; if sugar is present, the fasting blood glucose should be determined. If edema develops, place the patient on a low sodium diet; diuretics may be employed when strict sodium restriction is impossible. Potassium supplements should be administered in cases of prolonged use. Treatment with SYNACTHEN DEPOT should be terminated gradually. Patients who are subjected to the stress of surgical operations or trauma while being treated, or within one year after treatment has been terminated, should have their SYNACTHEN DEPOT therapy augmented or reinstated and continued for the duration of the stress period and immediately following it. Where there is a history of peptic ulcer, an ulcer regimen is recommended prophylactically; if gastric symptoms are experienced during the course of treatment, X-ray examination should be done. Infections must be treated simultaneously with appropriate antibiotics; it should be borne in mind that signs and symptoms of inflammation may be masked by the antiinflammatory effects of cortisol produced by the overactive adrenal glands.
The patient is a white girl born in 1955 who was 13 years old at the time the diagnosis was made. Her parents were related as shown in the family tree in Fig. 1. Both parents were 26 years old at the time of the patient's birth. The mother is in good health; the father died accidentally. The patient is the younger of two surviving children. Her older brother is of normal intelligence and in good health but because of emotional maladjustment he has been attending a child guidance clinic for several years. The last pregnancy, one year after the patient was born, terminated at 51/2 months in the stillbirth of male twins. Their weights were 607 and 270 grams and no gross anomalies were detected at autopsy. The patient was born at term, weighing 3476 grams, following an uneventful pregnancy. Initial development was normal but there was marked photophobia at 6 weeks of age and the baby seemed unusually inactive and sleepy. During later infancy and throughout childhood she was admitted to hospital on numerous occasions. Persistent photophobia led eventually to the diagnosis of bilateral corneal erosions. Anisotropia and nystagmus were also noted. Recurring corneal ulcerations led to extensive investigations, including viral studies and histological examination of corneal scrapings, but the origin of the lesions remained obscure and treatment had limited success. Finally the corneal erosions healed spontaneously at the age of 4 years at which time her squint was
surgically corrected.t A more persistent problem was presented by the skin lesions which
first appeared at the age of 8 months as blisters and warty growths on the flexor aspects of the fingers, the palms and the soles of the feet. Despite continuous treatment the lesions became worse and persisted as clusters of hyperkeratotic verrucous papules, with deep fissures and at times sup-, puration. A skin biopsy was consistent with the diagnosis of a localized form of congenital ichthyosoform erythroderma.
Growth and development The psychomotor development of the child was delayed although growth was normal. She did not hold her head up until 10 months of age; she sat without support at 15 months, walked at 2 years and talked at 3 years. She walked on the outer edges of the feet because of the painful callosities and ulcers on her soles. At the age of 9 years she was admitted to the institution for the retarded. Following identification of tyrosinosis some four years later, the patient was transferred to the University Hospital for investigation. Her appearance at the time of diagnosis is shown in Fig. 2. On admission she was agitated, negativistic and impulsive and she would scream and bite her arms. Her mood was labile, shifting from anger and rage to giggling euphoria. Psychological testing was difficult but her I.Q. was estimated to be 40 to 45. On physical examination a pendular horizontal nystagmus, a mild squint and the chronic skin disorder were
tSince submission of this report new data have been published indicating that corneal erosions in infancy may be caused by abnormal tyrosine metabolism (BURNS R: Am J Ophthalmol 73: 400, 1972).
Adverse Reactions Fluid retention, weight gain, mental changes (euphoria insomnia), gastric pain, acne, hyperglycemia and
or
Cushing's syndrome, skin pigmentation, facial flushing and hypertension. Adverse reactions, when they occur, are reversible on discontinuing treatment. Symptoms and Treatment of Overdosage Edema and hypertension during therapy usually indicate overdosage. In such cases the dosage should be reduced, frequency of administration decreased, or the drug withdrawn according to the severity of the condition. There is no known antidote for corticotrophin. Toxic effects should be treated symptomatically.
Dosage and Administration In general, the correct dose is the smallest one given at the longest possible interval necessary to produce control of the clinical disorder. For precise dosage and route of administration, please refer to the Package Insert or Product
~~~~~TYROSINOSIS
Monograph.
Availability
* CLEFT PALATE
Ampoules: Each containing 1 mg cosyntropin as zinc hydroxide complex in 1 ml distilled water. Vials: Each containing 2 mg cosyntropin as zinc hydroxide complex in 2 ml distilled water. To be stored at 46° -59° F away from light, and used before expiry date as shown on the label. Complete Prescribing Information is available upon request.
r
INDEX CASE C-3074 DORVAL QUEBEC
CATARACTS t GLAUCOMA I J TOTAL NORMAL MALES & FEMALES oUUNAFFECTED OR UNKNOWN e
FIG. 1-The family tree of the patient. The inbreeding coefficient of the patient is 4( )7= 1/32, giving the degree of relationship for her parents as halfway between first and second cousins. C.M.A. JOURNAL/FEBRUARY 17, 1973/VOL. 108 479
observed. She was well developed measured using gas-liquid chromato¬ and the total tyrosyluria was physically for her age (weight 47 kg., graphy determined circumference head 157 by the method of Medes.1 cm., height While the patient was receiving a 53.5 cm.). She had black hair, dark brown eyes and she always looked normal diet her plasma tyrosine was suntanned even with minimal ex¬ 25 mg./lOO ml. (normal < 2.5) and posure to sun. No other abnormality the urinary tyrosine was 0.4 mg./mg. creatinine. The tyrosine content of the was detected and, specifically, there was no evidence of liver or kidney cerebrospinal fluid was 8 mg./lOO ml. The total tyrosyluria was 2.4 mg./mg. or rickets, neurological dysfunction, creatinine. The urinary free tyramine disorders. was increased to 6 ng/mg. creatinine. When challenged with a tyrosine Investigations load of 0.25 mM (45 mg.) per kg. Electroencephalographic findings were body weight, the plasma tyrosine level within normal limits. Radiographs of rapidly rose to 50 mg./lOO ml. with¬ chest and skull and intravenous pyelo¬ in one hour of ingestion. There was gram were normal. Skeletal survey also a marked increase in the urinary showed a normal bone age but there excretion of tyrosyl compounds during were unusual vertical striations in the the subsequent 24 hours, the urinary distal end of each femur which were tyrosine was increased to 1.0 mg./ still present in repeat films one year mg. creatinine and the total tyrosylu¬ later.17 The results of the usual labo¬ ria was 4.0 mg./mg. creatinine. Both ratory investigations of blood, urine plasma tyrosine and urinary tyrosine and cerebrospinal fluid were normal. metabolites returned to the pre-load levels during the following 48 hours. The plasma and urinary amino-acid Special biochemical investigations levels, other than tyrosine, were with¬ The tyrosine content of the capillary in the normal range. blood and urine was determined by Administration of 1 g. ascorbic paper chromatography. Venous blood acid per day for 10 days while the and urine were examined using a patient was on a normal diet did not Technicon Amino-Acid Analyser. The influence the plasma tyrosine level or individual phenolic acids in urine were tyrosyluria, indicating that the meta¬ bolic abnormality was not a result of ascorbic acid deficiency.3'5 Details of the biochemical proce¬ dures and studies in this case have been published elsewhere.18
Treatment and progress An experimental dietary
regimen with restricted tyrosine-phenylalanine in¬ take and supplementary amino acids was started with the objective of normalizing the patient's blood tyrosine and observing any clinical and meta¬ bolic effects of such a diet. An investigational product, 3200AB*, was used to provide the basic protein equivalent. The minimal daily requirements of combined phenylala¬ nine and tyrosine in an adult have been calculated as 1000 mg./24 hrs.19 and up to 70% of phenylalanine may be converted into tyrosine. The requirement for a developing teenager is higher and in our patient the diet was calculated so that she would re¬ ceive no more than 1 g. phenylalanine and 1 g. tyrosine per 24 hours. There were many practical prob¬ lems in making such a diet accept¬ able to a strong, uncooperative retard¬ ed teenager but all the problems were successfully resolved within the first three weeks of treatment. This necessitated invention of suitable recipes FIG. 2.The of diagnosis.
patient
480 CMA.
JOURNAL/FEBRUARY 17, 1973/VOL. 108
at the time
?Provided through the courtesy of Mead Johnson Canada Ltd.
by the dietitian, assay of tyrosine values in some foods since the exist¬ ing tables were incomplete, and use of operant conditioning techniques to induce acceptance of the formula by the patient. Details of this dietary therapy and the experience of the first three months of treatment have been reported elsewhere.20 The diet was continued for 14 months and throughout that period the plasma tyrosine and urinary tyro¬ syl concentrations were maintained at near normal levels. The only devia¬ tions from this routine were occasion¬ al food challenges or experimental loads given under controlled condi¬ tions. Demonstration of the feasibility of the use of such a long-term diet in an older patient was of value and her growth and nutrition remained satis¬ factory. It was also hoped that the normalization of the blood tyrosine level might decrease her irritability and behaviour disorder. Her mental functions were unchanged but after some four months of treatment the patient was less irritable and needed fewer tranquillizers. The improvement in behaviour could not, however, be considered a direct cerebral response to normalization of tyrosine meta¬ bolism but, rather, a secondary result of the lessening of her discomfort when the condition of the skin on her hands and feet improved markedly for the first time since infancy. After five months of treatment the skin le¬ sions completely disappeared. The skin looked quite healthy except for
a slight glossiness and hyperemia. The patient was happier and able to walk without discomfort. The skin remained healthy through the remaining nine months of therapy. When the experimental diet was eventually abandoned the metabolic imbalance returned immediately and after four months of regular diet the skin condition of the hands and feet began to deteriorate and soon regressed to the pre-diet state. It is tempting to assume that there is a direct causative relationship be¬ tween the variant of congenital ichthyosoform erythroderma noted in our patient and her abnormal tyrosine metabolism. The implications of this
observation
are
discussed elsewhere.21
Investigation of other members of the family
Only the patient's mother and mater¬ grandmother were available for complete investigation. The same bat¬ tery of tests including radiology were performed but all gave normal values. A tyrosine loading test for demonstranal
tion of heterozygosity gave an equivocal result. Single specimens of blood and urine were available from the patient's brother but showed no biochemical
of undetermined
abnormality.
tient was examined at the age of lOVi years. In the third case described13'14 there were similar features, most notably absence of liver or kidney involvement in the presence of high plasma tyrosine and tyrosyluria. Clinically the child presented with mental retardation and multiple congential anomalies including mi-
Discussion Diagnosis of tyrosinosis can be made in the first weeks of life. Early iden¬ tification is important for the family and for the child, especially in acute cases in view of the potential for
etiology occurring during infancy, seizures, nystagmus, hyperactivity and mental retarda¬ tion. There was no evidence of liver or kidney dysfunction when the pa¬
dietary management. Diagnostic screening can be done using the nitrosonaphthol test on crocephaly. It is interesting to note the fre¬ urine. Others such as the ferric chloride or dinitrophenylhydrazine quency of ocular problems in this test are not reliable since they de¬ form of tyrosinosis. The patient of pend on PHPPA which may be ab¬ Wadman had early cataracts, Hol¬ ston's patient had a history of severe sent, as it was in our case. Biochemical and clinical confirm¬ keratitis and in our patient there ation of the diagnosis in most of the were stubborn corneal erosions dur¬ acute cases of tyrosinosis will pre¬ ing childhood. In addition, nystag¬ sent no difficulty, especially when mus was present in two of the pa¬ there are signs of hepatic and renal tients and it has also been reported tubular failure. During early infan¬ as occurring frequently in cases of cy some confusion might exist as to acute tyrosinosis.23 Skin lesions, whether tyrosinemia and tyrosylu¬ which in our case responded to ria observed in a baby are of the the phenylalanine-tyrosine-restricttransient variety or represent tyro¬ ed diet, have not been previously sinosis without hepatorenal disease. reported in tyrosinosis.21 The peculiar streakiness of the If such doubt exists it can usually be clarified by observing the infant's femora observed on radiographs of response to temporary protein re¬ our patient is probably an unrelat¬ striction and to a large dose of as¬ ed anomaly for which we have no corbic acid but in some cases the explanation.17 It has been reported recently that clinical observation and testing of in some treated cases of acute tyro¬ plasma and urine for tyrosine and sinosis the plasma tyrosine level re¬ its metabolites may have to be con¬ mains normal on termination of tinued for up to 10 months.3"5,22 Clinically our case is similar to treatment. A previously treated case the one described by Madman et of acute tyrosinosis was followed aP2 and to that reported more re¬ up by Gaull et aP* for 18 months cently by Holston and his col¬ while on a normal diet ad libitum; leagues,15 and probably the patient normalin concentrations of all amino of Campbell et al13 and Buist, Camp¬ acids the plasma were found. A bell and Koler14 belongs to the same similar experience was reported by category. Medes' case1 probably be¬ Harries et al.25 In our patient biochemical abnor¬ longs also to this group although there are clinical and biochemical malities were not self-limiting and differences which at present cannot returned immediately when the diet was discontinued. be explained. Current concepts of tyrosine me¬ Wadman's patient was an 18-yearold mentally retarded girl who had tabolism involve the major degrada¬ tion pathway of PHPPA to homono signs of disturbed liver function or of renal tubular defects. At the gentisic acid and additional degra¬ dation of 17 she had along other pathways to age years developed bilateral cataracts. She presented melanin, norepinephrine and epinewith tyrosyluria and a high blood phrine, and thyroxine. A dysfunction in tyrosine meta¬ tyrosine but otherwise her plasma amino-acid concentrations were nor¬ bolism along the major pathway has been identified in several patients mal. The salient clinical findings in having tyrosinosis with hepatorenal Holston's case were severe keratitis disease, suggesting a block at the 482 C.M.A. JOURNAL/FEBRUARY 17, 1973/VOL. 108
level of PHPPA-oxidase, and the deficient activity of liver PHPPAoxidase has been measured.26"28 The etiology of tyrosinosis is, however, much more complex than a simple genetically determined ab¬ sence of the enzyme PHPPA-oxi¬ dase activity which had been postulated in some earlier reports. Doubts about the specificity of a deficiency of PHPPA-oxidase in hereditary ty¬ rosinosis were first raised by Woolf9 on clinical grounds when he pointed out the benign course of neonatal tyrosinemia. Evidence that PHP¬ PA-oxidase deficiency was not of. primary importance was substantiated by Gaull et al.24 Methioninemia in acute hereditary tyrosinosis presented a problem for the PHP¬ PA-oxidase deficiency hypothesis. GaulFs studies of transsulfuration in liver showed that the decreased ability to metabolize methionine in patients with acute hereditary tyro¬ sinosis cannot be due to loss of functioning liver tissue alone but is associated with specific inhibitions or deficiencies of methionine-activating enzyme and cystathioninesynthetase of the liver. Perry et aP° demonstrated that tyrosine-fed pigs exhibited marked tyrosinemia and tyrosyluria but did not show any elevation of plasma concentration of methionine. They failed to develop either hypoglyce¬ mia or gross aminoaciduria which is usually present in human cases of acute tyrosinosis. By contrast, methionine-fed pigs developed tyrosine¬ mia, tyrosyluria, gross aminoacidu¬ ria and severe hypoglycemia. The results suggest that tyrosinosis with methioninemia in man may not be due simply to an error in tyrosine degradation but may represent some unrecognized error in methionine or carbohydrate metabolism or some other hepatic disease. The plasma tyrosine concentra¬ tions in our patient and in other known cases of tyrosinosis without hepatorenal disease were higher than those concentrations usually reported in tyrosinosis with hepato¬ renal disease, suggesting that the nature or degree of the metabolic block may be different in the two forms. The fact that our patient as well as three others12"15 had a long-standing and marked tyrosinemia and ty¬ rosyluria without hepatic or renal disease makes unacceptable the
suggestion that the hepatorenal disease is secondary to the accumulation of tyrosine and its metabolites. Tyrosinosis with hepatorenal disease may be a different disorder and the deficient PHPPA-oxidase activity and related biochemical abnormalities in that condition could be secondary to an unusual form of hepatic destruction. The biochemical findings reported in our case could be due to a defect in PHPPA-oxidase. However, so far the only enzymatic studies of tyrosinosis without hepatorenal disease, reported by Fellman et apl and more recently by Kennaway and Buist,8' showed deficient activity of soluble tyrosine transaminase. The cause of the mental retardation in our patient is unknown. It seems that in our patient, as well as in the three earlier reported cases,""5 there is a primary genetic defect in tyrosine metabolism and that these cases represent "essential
tyrosinemia". The authors wish to thank Dr. J. A. Beddie, Dr. J. Lacny, Mrs. A. Clark, Mrs. H. Anderson and the nursing staff of the Saskatchewan Training School in Moose Jaw for their help and cooperation; and Jayne MacAulay, R.T., and Donna Fraser, R.P.N., for technical assistance. Finally, we would like to thank Dr. Elizabeth Ives for preparing the family tree and for constructive criticism of the manuscript.
Risum6 La tyrosinose: une nouvelle forme L'article etudie les anomalies du metabolisme de la tyrosine a quatre points de vue differents: (1) accumulation de tyrosine et de ses metabolites, secondaire a une lesion hepatique severe, a une avitaminose C, etc.; (2) la tyrosinemie neonatale transitoire; (3) la tyrosinose hMr& ditaire accompagnee de dysfonction hepatorenale, oiu l'augmentation de la teneur plasmatique en tyrosine et en m'thionine peut repr'senter des manifestations secondaires a une pathologie inconnue; et (4) la "tyrosinemie essentielle" ou tyrosinose, sans dysfonction hepatorenale, qui peut representer une defectuositm primaire du metabolisme de la tyrosine. L'article presente un nouveau cas de tyroxsinose, exempt de dysfonction hepatorenale, chez une fillette
de 13 ans, souffrant d'arrieration mentale. Il expose les constatations cliniques, les resultats des analyses de laboratoire et ceux d'un traitement dietetique permettant de normaliser les concentrations plasmatiques de tyrosine et de ses metabolites urinaires et compare ces donnees aux caract6ristiques de trois cas similaires releves dans la litt&rature. Les auteurs estiment que ces cas constituent la "tyrosin6mie essentielle", oiu le defaut primaire dans le metabolisme de la tyrosine peut etre d'origine gen6tique. References 1. MEDES G: A new error of tyrosine metabolism: tyrosinosis. The intermediary metabolism of tyrosine and phenylalanine. Biochem J 26: 917, 1932 2. LEVINE RJ, CoNN HO: Tyrosine metabolism in patients with liver disease. J Clin Invest 46: 2012, 1967 3. AVERY ME, CLow CL, MENKES JH, et al: Transient tyrosinemia of the newborn: dietary and clinical aspects. Pediatrics 39: 378, 1967 4. WONG PWK, LAMBERT AM, KOMROWER GM: Tyrosinemia and tyrosyluria in infancy. Dev Med Child Neurol 9: 551, 1967 5. LEvy HL, SHIH VE, MADIGAN PM, et al: Transient tyrosinemia in fullterm infants. JAMA 209: 249, 1969 6. GJESSING LR (editor): Symposium on tyrosinosis. Oslo, Oslo University Press, 1966 7. KOGUT MD, SHAw KN, DONNELL GN: Tyrosinosis. Am J Dis Child 113: 47, 1967 8. SCRIVER CR, SILVERBERG M, CLOW CL: Hereditary tyrosinemia and tyrosyluria. Can Med Assoc J 97: 1047, 1967 9. SCRIVER CR, LAROCHELLE J, SILVERBERG M: Hereditary tyrosinemia and tyrosyluria in a French-Canadian geographic isolate. Am J Dis Child 113: 41, 1967 10. FAIRNEY A, FRANcIS D, ERSSER RS, et al: Diagnosis and treatment of tyrosinosis. Arch Dis Child 43: 540, 1968 11. PARTINGTON M, SCRIVER CR, SAssKORTSAK A (editors): Conference on hereditary tyrosinemia. Can Med Assoc J 97: 1045, 1967 12. WADMAN SK, VAN SPRANG FJ, MAAs JW, et al: An exceptional case of tyrosinosis. J Ment Defic Res 12: 269, 1968 13. CAMPBELL RA, BUIST NR, JACINTO EY, et al: Supertyrosinemia (tyrosine transaminase deficiency), congenital anomalies and mental retardation. Presented at 37th Annual Meeting of Society for Pediatric Research, 1967
484 C.M.A. JOURNAL/FEBRUARY 17, 1973/VOL. 108
14. BUIsT NR, CAMPBELL RA, KOLER RD: Hepatic soluble tyrosine transaminase deficiency (abstract). Excerpta Med 191: 32, 1969 15. HOLSTON JL, LEVY HL, TOMLIN GA, et al: Tyrosinosis: a patient without liver or renal disease. Pediatrics 48: 393, 1971 16. PERRY TL, HANSEN S, MACDOUGALL L: Urinary screening tests in the prevention of mental deficiency. Can Med Assoc J 95: 85, 1966 17. ZALESKI WA, HOUSTON CS, HILL A: Unusual radiological changes in tyrosinosis. Lancet 11: 46, 1972 18. HIL A, ZALESKI WA: Tyrosinosis: biochemical studies of an unusual case. Clin Biochem 4: 263, 1971 19. DEMOPOULOS HB: Effects of reducing the phenylalanine-tyrosine intake of patients with advanced malignant melanoma. Cancer 19: 657, 1966 20. HILL A, NORDIN PM, ZALESKI WA: Dietary treatment of tyrosinosis. J Am Diet Assoc 56: 308, 1970 21. ZALESKI WA, HILL A, KUSHNIRUK W: Skin lesions in tyrosinosis: response to dietary treatment. Br J Dermatol 88: 1973 (in press) 22. PARTINGTON MW, DELAHAYE DJ, MASOrn RE, et al: Neonatal tyrosinemia: a follow-up study. Arch
Dis Child 43: 195, 1968 23. FRANCOIS R, QUINCY C, RIEDWEG M, et al: Encephalopathie congenitale familiale associee a une anomalie du metabolisme de la tyrosine. Pe'diatrie 17: 955, 1962 24. GAULL GE, RASSIN DK, SOLOMON GE, et al: Biochemical observations on so-called hereditary tyrosinemia.
Pediatr Res 4: 337, 1970
25. HARRIES JT, SEAKINS JWT, ERSSER RS, et al: Recovery after dietary treatment of an infant with features of tyrosinosis. Arch Dis Child 44: 258, 1969 26. SCRIVER CR, DAVIES E: Investigation in vivo of the biochemical defect in hereditary tyrosinemia and tyrosyluria. Can Med Assoc J 97: 1076, 1967 27. LA Du BN: The enzymatic deficiency in tyrosinemia. Am J Dis Child 113: 54, 1967 28. GENTZ J, HEINRICH J, LINDBLAD B, et al: Enzymatic studies in a case of hereditary tyrosinemia with hepatoma. Acta Pediatr Scand 58: 393,
1969
29. WOOLF KI: Tyrosinosis (inborn hepato-renal dysfunction). Proc R Soc Med 59: 814, 1966 30. PERRY TL, HARDWICK DF, HANSEN S, et al: Methionine induction of experimental tyrosinemia. J Ment Defic Res 11: 246, 1967 31. FELLMAN JH, VANBELLINGHEN PJ, JONES RT, et al: Soluble and mitochondrial forms of tyrosine aminotransferase. Relationship to human tyrosinemia. Biochemistry 8: 615, 1969 32. KENNAWAY NG, BUIST NR: Metabolic studies in a patient with hepatic cytosol tyrosine aminotransferase deficiency. Pediatr Res 5: 287, 1971
