Three aminoacidopathies of the late infantile and early childhood period—PKU, tyrosinemia, and Hartnup disease—are described here because of their clinical importance and because they exemplify different types of biochemical defects. Reference is also made to certain other aminoacidurias, described in the first part of this chapter, which, like Hartnup disease, are associated with intermittent ataxia. Only passing comments are made about the other aminoacidurias, which are exceedingly rare or have only an uncertain effect on the nervous system. A detailed account of these disorders can be found in the monograph of Scriver and coworkers.
The Phenylketonurias (Phenylalanine Hydroxylase Deficiency, PAH Mutation)
Apart from being the most frequent of the aminoacidurias, this entity has a special historical significance. Since its discovery by Følling in 1934, it has remained the classic example of an aminoaciduria and illustrates three principles of medical genetics: first, it is inherited as an autosomal recessive trait; second, it exemplifies Garrod’s cardinal principle of gene action, in which genetic factors specify chemical reactions as well as biochemical individuality; third, PKU is expressed only in an environment that contains an abundance of l-phenylalanine. Thus, as predicted by Galton, the ultimate phenotype is a product of “nature and nurture” (Scriver and Clow).
One must refer to the phenylketonurias in the plural, for there are (1) the usual type and several mild and severe variants thereof, in all of which mental retardation is invariable if the disease is not treated early in life; (2) other types, presumably allelic mutations, in which there is hyperphenylalaninemia without PKU and without effect on the nervous system; and (3) a rare adult type with a progressive spastic paraparesis or without neurologic manifestations. Also there are a small number of patients (3 percent in our series) in whom a lowering of the hyperphenylalaninemia does not prevent the progression of the neurologic lesion.
At birth, the typical PKU infant is believed to have a normal nervous system. The disease appears later, only after long exposure of the nervous system to phenylalanine (PA), because the homozygous infant lacks the means of protecting the nervous system. However, if the mother is homozygous with high PA levels in the blood during pregnancy, the CNS is damaged in utero and the heterozygous infant is mentally defective from birth.
In the classic form of PKU, the impairment of psychomotor development can usually be recognized in the latter part of the first year, when expected performance lags. By 5 to 6 years in an untreated child, when the IQ can be estimated, it is usually less than 20, occasionally 20 to 50, and exceptionally above 50. Hyperactivity, aggressivity, self-injurious behavior—including severe injury to the eyes, clumsy gait, fine tremor of the hands, poor coordination, odd posturings, repetitious digital mannerisms and other so-called rhythmias, and slight corticospinal tract signs stand out as the main clinical manifestations. Athetosis, dystonia, and frank cerebellar ataxia have been described but must be rare. Also, seizures occur in a small minority of severely affected patients, taking the form at first of flexor spasms and later of absence and grand mal attacks. Most PKU patients are blue-eyed and fair in skin and hair color, and their skin is rough and dry and subject to eczema. A musty body odor (because of phenylacetic acid excretion) can often be detected. Two-thirds are slightly microcephalic. The fundi are normal, and there is no visceral enlargement or skeletal abnormality.