DISTURBANCES OF NEURAL FUNCTION IN THE PRESENCE OF CONGENITAL DISORDERS 



'9 r 5 



listed as new, but as expected and predictable on 

 genetic grounds." 



INBORN ERRORS OF METABOLISM 



A number of conditions affecting the development 

 of the nervous system show themselves primarily as 

 abnormal forms of bodily chemistry with or without 

 anatomic abnormalities. They may exist because an 

 enzyme system failed to develop, or they may result 

 because metabolic pathways are present that lead to 

 accumulations of abnormal metabolites. A number of 

 disorders occur in which the histiocytes and other 

 cells continue to manufacture certain fatty substances 

 that in turn may accumulate in the tissues, including 

 neurons, or they may otherwise affect neural func- 

 tion by means which are presently obscure (32). 

 Among these are Tay-Sachs amaurotic family idiocy 

 in which the nervous tissue is selectively affected 

 early in life by the intraneuronal accumulations of 

 gangliosides made by the neurons themselves (22). 

 These accumulations cause degeneration and often 

 destruction of the cells. In the infantile type of the 

 disease, the child shows gradual impairment of vision, 

 then blindness; this is accompanied by mental 

 deterioration progressing to idiocy and paralysis of 

 the limbs and bodv. 



Another developmental abnormality, which In- 

 comes manifest in the teens, is Wilson's disease or 

 hepatolenticular degeneration, characterized by an 

 inborn error of copper and alpha aminoacid metab- 

 olism. When the disease has developed, there is diffuse 

 gliosis of the brain, especially the lenticular nucleus, 

 and hepatic fibrosis, and a copper-containing pigment 

 discolors the iris. Ceruloplasmin, a plasma protein 

 that binds copper normally, is deficient in these 

 patients and plasma copper may also be low. However 

 what copper is present may be improperly bound 

 and this may be why it is more easily deposited in 

 tissues than normal. Whether this is directly related 

 to the aminoacid disorder (aminoaciduria) is ob- 

 scure (12, 33). 



Still other examples of inborn errors of metabolism 

 in which the nervous system is affected are illustrated 

 by Thomsen's disease or myotonia congenita which 

 is accompanied by some structural defects in other 

 organs, familial periodic paralysis in which a dis- 

 order of potassium metabolism is present, pernicious 

 anemia, and myasthenia gravis. There are many 

 others but these are cited to emphasize again the 

 diversity. 



Phenylketonuria 



This disorder, also called phenylpyruvic oligo- 

 phrenia, is a disease due to an inborn error of metabo- 

 lism that has attracted much attention and study 

 (20). It is characterized from the time of birth by 

 various grades of mental deficiency and by the excre- 

 tion of phenylpyruvic acid in the urine. The condition 

 appears to be caused usually by a single recessive 

 gene. There are no consistently found gross or micro- 

 scopic structural changes in the nervous system that 

 can be correlated with the mental defect and the only 

 consistently related characteristic (90 per cent) is a 

 blond complexion: fair hair and skin, and blue eyes. 

 Abnormally high amounts of phenylalanine and its 

 derivatives are present in the body fluids and the 

 evidence favors the view that the metabolic error lies 

 in a block in the enzymatic conversion of phenyl- 

 alanine into tyrosine. Precisely what steps are in- 

 volved is still debatable. The norm.]] enzyme svstem 

 that makes this conversion is absent in the liver of 

 phenylketonurics. In normal people but not in 

 phenylketonurics the ingestion of phenylalanine is 

 followed by a brief rise in blood tvrosinc-like sub- 

 stances [sotopically labeled phenylalanine can be 

 shown to be incorporated into the proteins of normal 

 individuals as tyrosine-like substances, but this docs 

 not happen in phenylketonurics. 



Disturbances of neural function are characterized 

 by mild in sr\ ere mental deficiency , that is, low grade 

 intelligence, but there are no distinctive patterns. 

 In exceptional cases the affected individuals can get 

 along outside of institutions and make a living to sup- 

 port a family About one-third of phenylketonurics 

 show no other nervous system abnormality while 

 another third exhibit such signs as mild muscular 

 hypertonicity, hyperactive deep reflexes, awkward 

 gait, slight tremors and occasional irregular motions 

 In the remaining third a stooped posture, rigid gait, 

 hypertonic muscles and hyperreflexia may be found, 

 and tremors of the hands sometimes with purposeless 

 movement occur. A variety of other occasional find- 

 ings are reported but they are too inconsistent to be 

 characteristic. Convulsive episodes are however a 

 feature of phenylketonuria, although the episodes in 

 any given patient are rare. 



Despite the fact that phenylketonuria has been a 

 popular subject for study because some aspects of its 

 biochemical genetics are well defined, the relation of 

 mental deficiency to phenylalanine is less clear. Does 

 the accumulation of phenylalanine cause the poor 

 neural function? Or are the mental defect and the 

 accumulated metabolite two different end results of a 



