Medical Progress Disorders of Amino Acid Metabolism 1971 JOHN H. MENKES, M.D., Los Angeles OVER THE PAST TWENTY YEARS the number of dis- The metabolic defect in PKU is a failure in the orders to which we are able to assign a known hydroxylation of phenylalanine to tyrosine. Phen- enzymatic defect in amino acid metabolism has ylketonuric children are born with only slightly increased strikingly. Even so, they are relatively elevated phenylalanine blood levels, but due to uncommon, and their importance lies, in part, in inactivity or absence of phenylalanine hydroxyl- the insight they offer into the normal develop- ase, the amino acid derived from food proteins ment and function of the human nervous system. accumulates in serum and cerebrospinal fluid In some of the disorders, such as cystathioninuria, and is excreted in large quantities. In lieu of the hyperprolinemia and hydroxyprolinemia, the as- normal degradative pathway phenylalanine is sociation of a neurologic disturbance may be converted to phenylpyruvic acid, phenyllactic fortuitous and merely the result of subjecting acid and phenylacetylglutamine. The transam- retarded children, a highly selected group, to ination of phenylalanine to phenylpyruvic acid is biochemical examination. A survey of the normal sometimes deficient for the first few days of life, adult population for the incidence of inborn er- and the age when phenylpyruvic acid may be rors of amino acid metabolism is needed to deter- first detected varies from 2 to 34 days. From the mine which of the conditions mentioned in this first week of life on, o-hydroxyphenylacetic acid review represent harmless metabolic variants. is also excreted in large amounts. Alterations within the brain are non-specific, Phenylketonuria usually confined to white matter, and probably Phenylketonuria (PKU) is an inborn error of progress in severity with increasing age. They metabolism due to the inability to convert phen- include an interference with the normal matura- ylalanine to tyrosine; it produces mental retarda- tion of the central nervous system, defective tion, seizures, and imperfect hair pigmentation. myelination, and a cystic degeneration of white Folling in 1934 first called attention to the con- matter.2 dition.' Since then the disease has been found in Phenylketonuric infants appear normal at birth. all parts of the world, although it is rare in Ne- During the first two months of life, vomiting, of- groes or in Jews of European descent. Its fre- ten projectile, and irritability are frequent. By quency in the United States, as determined by four to nine months delayed intellectual develop- screening programs, is approximately 1 in 14,000. ment becomes apparent.3 In the classic case, It is transmitted as an autosomal recessive dis- mental retardation may be severe, precluding order. speech and toilet training, and the Intelligence Quotient is under 50. Seizures are common in From the Division of Pediatric Neurology, University of California, Los Angeles, Center for the Health Sciences, and the Veterans Admin- the more severely retarded. These usually start istration Hospital, Brentwood. Original research reported in this review is supported by Research before 18 months of age and may cease spon- Grants NB 06938 from the National Institutes of Health, and by grants from the National Genetic Foundation, and Childrens' Brain Diseases. taneously. During infancy they may take the Reprint requests to: Division of Pediatric Neurology, University of form of infantile spasms, and later grand mal at- California, Los Angeles, Center for the Health Sciences, Los Angeles, Ca. 90024 (Dr. J. H. Menkes). tacks. 14 OCTOBER 1971 * 115 * 4 TABLE 1.-Screening Tests for Metabolic Defects addition of a dilute solution of 2,4-dinitrophenyl- Ferric Nitro- hydrazine produces a copious yellow precipitate Condition Chloride DNPH prusside in both fresh and old specimens (Table 1). For Phenylketonuria Green + routine screening on infants a simple stick test Maple Syrup Disease Navy Blue + Tyrosinosis Pale Green + (Phenistix®) is available for use on wet diapers. (transient) Confirmatory evidence can be obtained by find- Histidinemia Green Brown + ing an elevation of plasma phenylalanine. These Hyperglycinemia Purple + Methylmalonic Aciduria Purple + may already be abnormal in the cord blood of Homocystinuria - + PKU infants, and rise rapidly within a few hours Cystinuria - + of birth. Inasmuch as there may be a delay in Glutathioninuria - + the appearance of phenylpyruvic acid, both the ferric chloride and the dinitrophenylhydrazine tests are inadequate for the diagnosis of PKU dur- The typical patient is blond and blue eyed, ing the neonatal period. A program for routine with normal, and often pleasant features. The screening involving the microbiological or spec- skin is rough and dry, and there may be eczema. trofluorometric estimation of blood phenylalanine A peculiar musty odor, attributable to phenyl- levels has been instituted in California.6 acetic acid, may suggest the diagnosis. Signifi- cant neurological abnormalities are rare, although The widespread use of screening programs to microcephaly, and a mild increase in muscle tone, detect the newborn infant whose blood phenyl- particularly in the lower extremities, may be pres- alanine concentration is higher than normal has ent. Older children are restless and hyperactive; uncovered several other conditions that are as- and are inclined to self-stimulative movements sociated with elevated blood phenylalanine levels of the body and hands.. In institutionalized pa- during the neonatal period.7 tients there may be intellectual deterioration, Aside from phenylketonuria a variant, previ- owing perhaps to environment, perhaps to the ously termed "atypical phenylketonuria," is the natural history of the disease. most common. On a normal protein intake pa- A variety of electroencephalographic abnor- tients with this condition have blood phenylala- malities has been found, but hypsarrhythmic pat- nine between 7 mg and 20 mg per 100 ml. This terns, recorded even in the absence of seizures, contrasts with the classic PKU patient whose phen- and single and multiple foci of spike and poly- ylalanine levels are 20 mg per 100 ml or higher. spike discharges are the most common.4 The gene distribution of this entity differs from Untreated PKU is not invariably accompanied that of phenylketonuria, with a relatively high by intellectual deficit. There are a number of prevalence amongst Jews of European descent. phenylketonuric persons with intelligence quo- Less commonly, a defect in phenylalanine hy- tients above 90, athough having classic biochem- droxylation is coupled with a temporary or per- ical features of the condition. Although the manent abnormality of phenylalanine trans- incidence of spontaneous abortions is high, a amination. In these patients the excretion of number of PKu women have had children; most phenylpyruvic and o-hydroxyphenylacetic acids of the offspring, although heterozygous for PKU, is inappropriately low for the serum phenylalanine showed prenatal and postnatal growth retarda- concentrations, and the ferric chloride test is neg- tion, microcephaly, severe intellectual delay, and ative on a normal diet and may become only in a few instances major congenital malforma- slightly positive during a phenylalanine load. In tions. It seems likely that the high amino acid yet another variant the phenylalanine tolerance level in the pregnant PKU mother may damage the improves gradually over the first few months of fetus.5 life, but while the ability to metabolize phenylal- in it is The diagnosis of PKU can be suspected from anine is greater than PKU, never normal. the clinical features of the disease and from the In addition, elevated blood phenylalanine lev- examination of the patient's urine by the addition els are observed in a large proportion of prema- of ferric chloride. In inadequately preserved ture infants, particularly those receiving a high specimens, phenylpyruvic acid decomposes and protein formula. In all these patients tyrosine the ferric chloride test becomes negative. The levels are decidedly increased as well. CALIFORNIA MEDICINE 15 The Western Journol of Medicine In view of the existence of these variants of pear and the electroencephalogram often reverts PKU, the diagnosis of PKU can only be made if the to normal. Abnormally blond hair regains its nat- following criteria are satisfied: ural color. The effects on mental ability are less * Blood phenylalanine 20 mg per 100 ml or clear-cut. In the experience of Fuller and Shu- greater, with normal blood tyrosine levels. man"1",2 treated PKU children fell into a tri-modal * In untreated infants a positive ferric chloride distribution with respect to their I.Q. The age test by 2 to 36 days of age. at which therapy was initiated did not determine * When the infant is temporarily returned to a into which of the three groups a given child fell. normal diet between four and nine months of age, However, infants under 18 months of age whose the blood phenylalanine concentration rises to 20 blood phenylalanine levels were maintained un- mg per 100 ml or higher, and he begins to excrete der 5 mg per 100 ml had a decrease in intel- phenylpyruvic acid. lectual performance. Patients who were started * After an acute phenylalanine load, the blood on treatment before six months of age, some of tyrosine concentration does not rise. whom may have had phenylalaninemia, were The distinction between PKU and phenylala- represented