Psychiatric illnesses devastate families and drain billions of dollars from the US economy each year. Patients and physicians need new treatment approaches and methods for early diagnosis, since early intervention has been shown to prevent long-term mental deterioration and even suicide. Genetic insight offers the best hope for such approaches.

Scientists and physicians have long suspected that mutated genes cause most psychiatric disorders, since such disorders frequently run in families, perhaps more than any other common disease. Sadly, conventional types of genetic analysis have not identified a single gene proven important in psychiatric illness in the general population. The only promising insight comes from studies of the Wolfram syndrome gene, since WS mutations may account for more than 7% of cases of some common mental illnesses.

THE WOLFRAM SYNDROME GENE – GENETIC INSIGHT INTO PSYCHIATRIC ILLNESS

In 1937, Dr. Donald Wolfram of the Mayo Clinic described four boys who had both diabetes mellitus (sugar diabetes) and optic atrophy (failure of the nerves from the eye to the brain). Patients who have both these disorders are said to have the “Wolfram syndrome (WS).”

Other problems WS patients may experience include (Diabetes Care 1995):

          - Their bladders may enlarge because of autonomic nerve failure, which can lead to renal failure;
          - They may make very dilute urine because part of the pituitary gland fails;
          - Many experience nerve deafness, ataxia, or seizures.

Wolfram syndrome patients -- with two mutated WS genes -- frequently have severe psychiatric illnesses, beginning in adolescence (Lancet 1990):

Paranoid delusions;
          - Auditory or visual hallucinations;
          - Violent, aggressive, or assaultive behavior;
          - Organic brain syndrome (dementia), particularly in the late stages of their illness;
          - Depression;
          - Suicide attempts;
          - Required psychiatric hospitalization.

WS patients exhibit aggressive, impulsive behavior. Some examples include one WS patient who jumped from a second story window and another who twice attempted to jump from a moving vehicle.

Patients get WS by receiving a mutated WS gene from each parent. The parents, who carry only one mutated WS gene, are called carriers or heterozygotes. Close blood relatives such as aunts, uncles, and grandparents have a 50-50 chance of carrying the mutated WS gene in their family.

As always, carriers of a single mutation (heterozygotes) for any recessive syndrome, such as the Wolfram syndrome, are relatively common in the population, making this potentially an important gene in understanding the cause of mental illness. The first evidence that WS mutations predispose carriers (heterozygotes) to severe psychiatric symptoms appeared in the American Journal of Psychiatry 1991: “Significantly more WS blood relatives had committed suicide or had a psychiatric hospitalization than spouse controls.”

Carriers of WS mutations are much more frequent among the blood relatives than among spouses who married into the WS family.

Dr. Swift’s research team followed up on this and asked members of WS families to fill out questionnaires that asked about their own psychiatric and behavioral problems.

WS blood relatives reported depression as their most frequent symptom. The following problems were also high on the list:

          - Alcohol/drug dependence;
          - Destructive outbursts;
          - Suicide attempts;
          - Hospitalization for mental illness;
          - Controlling thoughts;
          - Racing thoughts;
          - Confusion/memory loss.

Next, the rigorous Index-Test Method confirmed that mutations in the WS gene predispose to mental illness. Each of the subjects in the index-test analysis was selected because s/he had been hospitalized for psychiatric illness. Hospitalization is solid evidence for such illness. When the psychiatric illnesses in the subjects were tabulated, it turned out that all of these subjects had been hospitalized for depression. Thus, the Index-Test Method confirmed that WS mutation carriers have a substantially increased risk for hospitalization for depression. This method has not yet been used to determine which other psychiatric disorders are associated with WS mutations.

Other research groups have published evidence that WS mutations are frequent in psychiatric patients. A substantial number of WS missense mutations were found in a mixed group of patients, including many with schizophrenia Another group found the same type of mutations in people who had committed suicide. One cannot draw definitive conclusions from these studies or other with similar research designs.

Testing for WS mutations will lead to earlier diagnosis of psychiatric conditions and, consequently, to early and successful intervention. For example, close relatives of a person who committed suicide could be tested to see if they carry a WS mutation. WS mutation screening can make it possible to diagnose a metabolic, as opposed to psychosocial, cause of a child’s severe behavioral problems. Proper treatment can then be given.

Before information about WS mutations can be utilized fully to improve the diagnosis and care of psychiatric patients, two major questions must be addressed. The index-test method must determine which psychiatric disorders, in addition to depression, arise from carrying a single WS mutation. Second, this method must be applied to find out which WS missense mutations are truly associated with psychiatric illness.

The ultimate goal, preventing psychiatric illness altogether in WS mutation carriers, will be achieved when scientists understand how such illnesses arise from the basic metabolic error caused by a WS mutation.

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