I was grateful to read about the efforts of Peterson and co-workers (1995), who provided a detailed case series and a review of the literature on neuroleptic malignant syndrome (NMS) in JCAP. However, the family neuropsychiatrie histories of their patients were not presented. Given the increasing evidence for a genetic predisposition to NMS, omitting the family history might miss potentially useful information that could shed light on the natural history of this condition. It is noteworthy that a major breakthrough in the pharmacogenetic explanation of malignant hyperthermia, an analog of NMS, started from uncovering a family history of multiple anesthetic deaths (Denborough et al. 1962). Otani et al. (1991) observed the co-occurrence of three cases of NMS in two generations of one family and suggested a dominant genetic transmission. Although a genetic marker for NMS has not been demonstrated, there is an increasing number of well-defined neurogenetic diseases that are associated with an increased risk for NMS. These conditions include Wilson's disease (Buckley et al. 1990), acute porphyria (Santosh and Malhotra 1994), late-onset Tay-Sachs disease (Rosebush et al. 1995), and senile dementia of the Lewy body type (McKeith et al. 1992). Moreover, a recurrence of NMS in the same individual with and without neuroleptic exposure has been observed (White 1992), and catatonía has repeatedly been associated with a stage in the progression toward NMS (McKeith et al. 1992, Rosebush et al. 1995, White 1992, Woodbury et al. 1992). The convergence of these observations underscores the heterogeneity of NMS and implies individual genetic vulnerability. Thus, elucidating the natural history of NMS might require a psychopharmacogenetic approach.Psychopharmacogenetics is defined as the discipline that encompasses a multidimensional analysis of genes, drugs, and behaviors in an attempt to provide guidance for optimum therapy and a preventive strategy (Tu 1994). The development of this notion can be based upon Motulsky's thesis (1957) that when an adverse drug effect occurs, the particular reaction suggests the possibility of a pharmacogenetic predisposition. The relevance of this approach to the study of NMS was illustrated by Kalow (1972), who found that malignant hyperthermia with rigidity is associated with a preexisting genetic trait. Since NMS and malignant hyperthermia share a common final pathway of skeletal muscle rigidity and hyperthermia (Caroff and Mann 1988), it is conceivable that a pharmacogenetic probe of NMS would be rewarding.Although the pathophysiology of NMS remains obscure, a low serum iron level has been observed in a number of these patients during the acute state (Rosebush et al. 1995, White 1992. Iron is a cofactor for a variety of enzymes essential for neuronal activity, so it is difficult to ignore the potential etiologic implications. This finding, along with the observation that the pathophysiology of acute porphyria is attributable to a central heme deficiency (Watson 1975), raises the possibility th...
