Wolframin mutations and hospitalization for psychiatric illness.

Genetic predisposition plays an important role in most common psychiatric disorders. The identification of a specific gene associated with a psychiatric illness can lead to improved management of the gene-associated disorder. Mutations in the wolframin gene are associated with mental illness. Many patients with the Wolfram syndrome (WS), who are homozygous or compound heterozygous for wolframin mutations, have severe psychiatric symptoms. In WS families, close blood relatives, who have a high probability of carrying a single wolframin mutation, had a statistically significant excess, over spouse controls, of psychiatric hospitalizations, attempted and completed suicides, and self-reports of mental illness. Since heterozygous carriers of wolframin mutations are relatively frequent in the population according to the general Hardy-Weinberg principle, such mutations might be responsible for the illnesses of many psychiatric patients. The hypothesis that heterozygous carriers of a wolframin mutation are predisposed to psychiatric illness was tested in subjects from 25 WS families. In all, 11 relatives who had psychiatric hospitalizations could be genotyped through mutation analysis. Eight of these carried the wolframin mutation transmitted in their family, significantly (one-sided P=0.0022) more than the 3.0 expected if there were no association between psychiatric hospitalizations and mutations at this locus. All eight mutation-positive subjects had been hospitalized for a major depression. This confirmation of the association is not influenced by confounders, undetected stratification, or genetic heterogeneity. The relative risk of psychiatric hospitalization for depression was estimated to be 7.1 (95% CI 1.9-26.6) for carriers of a single wolframin mutation compared to noncarriers.

Psychiatric disorders and mutations at the Wolfram syndrome locus.

Identifying genetic loci at which mutations predispose individuals to common psychiatric illnesses will have major impact on the diagnosis and treatment of mental illness. The available evidence indicates that mutations at the Wolfram syndrome locus contribute substantially to the prevalence of psychiatric illness in the general population. Patients with mutations at this locus on both parental chromosomes, called Wolfram syndrome homozygotes, have a distinctive and rare autosomal recessive syndrome characterized by juvenile onset diabetes mellitus and bilateral progressive optic atrophy. Diverse and serious psychiatric manifestations frequently have been observed in Wolfram syndrome patients; however, the population burden of mental illness attributable to mutations at this locus is almost entirely from individuals who carry a single mutation, called Wolfram syndrome heterozygotes, who have no distinguishing physical characteristics but constitute approximately 1% of the population. Molecular genotyping of blood relatives of Wolfram syndrome patients has shown that Wolfram syndrome heterozygotes are 26-fold more likely than noncarriers to have a psychiatric hospitalization. Severe depression was the predominant finding in the test group studied. The prediction that approximately 25% of all patients hospitalized for depression are Wolfram syndrome heterozygotes now can be tested by mutation screening of hospitalized patients from the general population. Many other behavioral and cognitive difficulties also have been observed in Wolfram syndrome families. For each specific psychiatric abnormality, a "test group" of blood relatives within Wolfram syndrome families with that abnormality can be formed. By comparing the number of Wolfram syndrome heterozygotes found in each test group by molecular genotyping with the number expected under the null hypothesis, the index-test method can determine which clinical phenotypes result from mutations at the Wolfram syndrome locus. This method can be utilized to identify other loci at which mutations predispose individuals to psychiatric illnesses.

Predisposition of Wolfram syndrome heterozygotes to psychiatric illness.

Identification of specific genes that predispose to psychiatric illness will lead to more precise psychiatric diagnosis and more effective treatment. Heterozygous carriers of genes for many autosomal recessive syndromes may be 1% or more of the general population. Thus, if mutations at a specific locus produce psychiatric manifestations in homozygous affected individuals, it is important to determine whether mutations at such a locus also predispose heterozygous carriers to psychiatric disorders. The hypothesis that heterozygous carriers of the gene for the Wolfram syndrome (WS) are predisposed to psychiatric illness was supported previously by the finding of an excess of psychiatric hospitalizations and suicides in WS blood relatives compared to spouse controls. This hypothesis has now been tested further by comparing the number of psychiatrically hospitalized blood relatives with the specific marker haplotype associated with the Wolfram syndrome gene in their families to the number expected under the null hypothesis, calculated from Mendelian inheritance principles and the estimated haplotype frequency. The proportion of psychiatrically hospitalized relatives who were WS carriers (10/11) was much higher than expected (3.1/11), leading to the provisional estimate that WS gene carriers are 26-fold more likely to require psychiatric hospitalization than non-carriers.

Morbidity and mortality in the Wolfram syndrome.

OBJECTIVE: To determine the major causes of morbidity and mortality in the autosomal recessive Wolfram syndrome, which is defined by diabetes and bilateral progressive optic atrophy with onset in childhood or adolescence. RESEARCH DESIGN AND METHODS: We abstracted and reviewed the medical records of 68 confirmed cases of Wolfram syndrome identified through a nationwide survey of endocrinologists, ophthalmologists, institutes, and homes for the blind. We also reviewed all available autopsy records. RESULTS: The most common causes of morbidity and mortality were the neurological manifestations of this syndrome and the complications of urinary tract atony. There was a lower frequency of diabetic ketoacidosis, no histologically proven diabetic glomerulosclerosis, and less severe, more slowly progressive, diabetic retinopathy than in classic type I diabetic patients. Mortality in Wolfram syndrome is much higher than in type I diabetes; 60% of Wolfram syndrome patients die by age 35. Recognition of these clinical differences from classic type I diabetes is important for the proper management of Wolfram syndrome patients. CONCLUSIONS: Identification of Wolfram syndrome patients among all diabetic patients presenting in childhood or adolescence is important because the management of patients with this syndrome is different from that of patients with classic type I diabetes.

Linkage of the gene for Wolfram syndrome to markers on the short arm of chromosome 4.

Wolfram syndrome is an autosomal recessive disorder defined by the occurrence of diabetes mellitus and progressive bilateral optic atrophy. Wolfram syndrome homozygotes develop widespread nervous system abnormalities; in particular, they exhibit severe behavioural difficulties that often lead to suicide attempts or psychiatric hospitalizations. The Wolfram syndrome gene also predisposes heterozygous carriers to psychiatric disorders, and may contribute significantly to the overall burden of psychiatric illness. Based on a linkage analysis of 11 families segregating for this syndrome using microsatellite repeat polymorphisms throughout the human genome, we found the Wolfram syndrome gene to be linked to markers on the short arm of human chromosome 4, with Zmax = 6.46 at theta = 0.02 for marker D4S431.

Psychiatric disorders in 36 families with Wolfram syndrome.

OBJECTIVE: The purpose of this study was to test the hypothesis that heterozygous carriers of the gene for the Wolfram syndrome, who constitute about 1% of the population, are predisposed to significant psychiatric illness. The Wolfram syndrome is an autosomal recessive neurodegenerative syndrome in which 25% of the individuals who are homozygous for the condition have severe psychiatric symptoms that lead to suicide attempts or psychiatric hospitalizations. METHOD: The authors collected questionnaires, death certificates, and hospital records for blood relatives and their spouses in 36 families of individuals with the Wolfram syndrome and compared the proportion of blood relatives who had had psychiatric hospitalizations, had committed suicide, or had self-reported mental illness to the proportion of spouses with the same manifestations. RESULTS: The proportion of blood relatives who had had psychiatric hospitalizations, had committed suicide, or had self-reported mental illness significantly exceeded the proportion of spouses with the same manifestations. CONCLUSIONS: Since heterozygous carriers of the gene for the Wolfram syndrome are 50-fold more common among the blood relatives than among the spouses, the larger proportion among blood relatives is evidence that heterozygous carriers of the gene for the Wolfram syndrome are predisposed to significant psychiatric illness.

Psychiatric findings in Wolfram syndrome homozygotes.

Diabetes mellitus and bilateral optic atrophy are the defining characteristics of the autosomal recessive Wolfram syndrome. Diabetes insipidus, neurogenic bladder, deafness, and other neurological manifestations are frequent. A review was made of the medical records of 68 Wolfram syndrome patients, aged between 8 and 43 years, identified by casefinding throughout the USA. 41 of the patients (60%) had episodes of severe depression, psychosis, or organic brain syndrome, as well as impulsive verbal and physical aggression. These symptoms were very severe in 17 patients (25%), of whom 12 required admission to a psychiatric hospital and 11 attempted suicide. We conclude that the Wolfram syndrome gene predisposes homozygotes to psychiatric illness.

Bid purchasing of pharmaceuticals.

The effects of bid purchasing of drug products by hospitals and the factors to consider in bid purchasing of pharmaceuticals are reviewed; further, the prices available with bid purchasing to a specific hospital in 1974 and 1977 are presented. Factors important for a successful bid purchasing system of pharmaceuticals are: (1) use of a formulary policy, (2) an effective procedure for handling bid purchasing and (3) criteria for evaluation of drug products. Significant differences were found between prices available with and without bid purchasing for 50 nonproprietary drug products in 1974 and for 19 products in 1977. Although monetary savings to hospitals do exist with bid purchasing of pharmaceuticals, the degree of savings is dependent upon the drug usage for that hospital.

Potential economic effets of a brand standardization policy in a 1000-bed hospital.

The potential economic effects of a brand standardization policy on 50 multiple source, nonproprietary drugs in a 1000-bed hospital which uses a unit dose drug distribution system were studied. Inpatient drug usage cost and inpatient drug inventory cost for the year 1974 were compared under the existing nonformulary system and a simulated formulary system of brand standardization. Drug usage cost was defined as expenditures made by the study hospital for drugs which were administered. Drug inventory cost was defined as the dollar value of drug inventory being stored for use in the hospital. Potential saving in excess of $35,000 for drug usage cost and $9,000 for drug inventory cost could have been realized with a brand standardization policy on 50 nonprietary drugs. The differences in costs were significant at the 0.005 level. It is concluded that a brand standardization policy can be effective means of reducing drug usage cost and drug inventory cost in a large hospital.