220 PHYSIOLOGIC GENETICS 



visible. 808 The degeneration continued in rdrd eyes, while normal eyes showed fairly 

 normal differentiation. This suggests local genie action. There was, however, some 

 delay in the rate of rdrd degeneration in vitro, which may have resulted from retardation 

 of autonomous development but which might also indicate that explantation removed 

 the eye from an humoral toxic effect in vivo. Although this experiment provides a 

 suggestion as to a site of original genie action, there is no clue as yet for any of these 

 mutants as to the nature of their metabolic error. 



A somewhat different situation exists in the study of hereditary muscular dystrophy 

 (dydy) in the mouse. Skeletal muscle is certainly the primarily affected tissue in this 

 disease since the nervous system appears entirely normal. 869 Detailed histopathology 

 demonstrates great similarity to other hereditary muscular dystrophies, and gives 

 evidence that there is a continuing attempt at muscular regeneration even in in- 

 dividuals severely affected. 1383 Studies of C 14 -glycine incorporation and turnover 

 corroborate this finding. 215 Progressive wastage results from an excess of destruction 

 over synthesis. Parabiosis experiments, with conjoined normal-dystrophic pairs, 

 indicate clearly that there is no humoral factor responsible for muscular breakdown. 1013 

 The defect is indigenous to the muscle itself, thus almost certainly a result of local 

 genie action. All of the differences observed are undoubtedly the result of difference 

 in a single genie pair. The mutation was first recognized as a deviation within an 

 inbred strain, and the distribution and frequency of dystrophy in pedigrees and in 

 offspring of ovaries transplanted from dystrophic females clearly demonstrated in- 

 heritance as a unit autosomal recessive. 869, 1281 Evidence is now at hand, from out- 

 crosses, repeated backcrosses, and linkage tests, that this substitution of a single genie 

 pair creates essentially the same syndrome of disease in combination with a great 

 variety of genetic backgrounds. 805 The defect is already apparent histologically at 

 two weeks postnatal, the first age at which the entity can be diagnosed from behavior. 

 At earlier stages study of muscular disease is difficult because normal muscle has not 

 yet assumed its adult form; this finding suggests that in muscular dystrophy, as in 

 previously described syndromes, the tissue defect may involve a failure to complete 

 normal differentiation. In contrast to the disease entities previously described, 

 however, there is a bewildering array of evidence of deranged metabolism. K/Na 

 balance is abnormal, 47 ' 683 creatine/creatinine balance is abnormal, 683, " 6 muscle 

 lipid is increased, 1200 distribution of lipoproteins and glycoproteins deranged, 968 

 myosin concentration decreased, 969 contractibility decreased, 1148 relaxation time 

 lengthened, 1148 and levels of activity of many enzymes altered. 10, 216, 217, 541, 1034, 1035, 

 1074. i3i4. 1372. 1468 j t a pp ears probable that many of these alterations occur when- 

 ever muscle is degenerating and thus are results rather than causes of the basic defect. 

 There is no guarantee that the character which is associated with a particular genie 

 substitution is the final stage in a path of genie action ; it may be an intermediate step, 

 and the recognized character may have extensive metabolic consequences. In a 

 situation with multiple metabolic changes, it is difficult to determine which defect is 

 primary. One helpful approach is retrograde analysis, attempting to find a metabolic 



