Dentatorubral-pallidoluysian atrophy (DRPLA) is a neurodegenerative disorder characterized by an unstable CAG trinucleotide repeat in the DRPLA gene on chromosome 12q12, leading to pathological changes in the brain.1,2 DRPLA is a rare condition with an estimated prevalence of 0.2—0.7/100,0003 population in Japan. Patients with DRPLA manifest various combinations of symptoms such as epileptic seizures, myoclonus, ataxia, and dementia.4,5 Patients sometimes develop psychiatric symptoms, which are often overlooked.6—8 Most previous reports dealing with such psychoses are lacking in genetic confirmation. Here we report four patients with DRPLA, confirmed by genetic identification of an expanded CAG repeat, who developed schizophrenia-like psychosis.
The four patients with psychosis were confirmed as having DRPLA by standard genetic testing.1,2 These patients represent 10% to 15% of the total patients with DRPLA treated in two national psychiatric hospitals. The main clinical and laboratory findings for these four patients are shown in t1.
Patient 1 was a Japanese man who died of multiple organ failure at age 64. His clinical symptoms to age 56 have been reported in part elsewhere.8
Neurological findings. The patient developed a finger tremor at age 40. By age 42, he showed mild dysarthria and unsteadiness. Cerebellar ataxia gradually progressed, his physical condition declined, and the patient was bedridden and required tube feeding by age 57. He demonstrated myoclonic seizures and generalized tonic-clonic convulsions at age 59.
Psychiatric findings. Starting at age 40, he became short-tempered and careless. At age 46, he experienced persecutory delusions. He thought that neighbors were trying to sue him and that they had assembled a group of hooligans to assault him. Furthermore, he described delusions of grandeur, believing himself, for example, to have discovered a perfect treatment for tinea. When he expressed these delusions, he was agitated but conscious. The delusions disappeared within 3 months with administration of haloperidol 4 mg/ day.
Patient 2 was a Japanese man who died of acute pneumonia at age 56.
Neurological findings. This patient showed fine finger tremor at age 39 and mild gait ataxia at age 43. He developed recurrent generalized seizures and severe truncal ataxia. He was bedridden by age 50 and was fed by gastric tube at age 52.
Psychiatric findings. He became short-tempered and frequently exhibited brief delusional moods (Wahnspannung) starting at age 45. He developed persecutory delusions, believing that hospital personnel were reporting him to the police as a criminal, that he was being watched by fellow patients as well as the police, and that his personal affairs were reported in the newspaper. These delusions faded with haloperidol administration (1.5—3 mg/day). Thereafter, his cognitive function and daily activity level declined steadily.
Patient 3 is a 35-year-old Japanese woman.
Neurological findings. This patient exhibited recurrent myoclonic seizures and mild gait ataxia starting at age 24. She had her first generalized seizure at age 25. At age 29, generalized seizures increased to one per day, and athetotic movements and dysarthria were noted.
Psychiatric findings. She had been short-tempered and had exhibited eating disorders and school phobia since age 14. Beginning at age 18, she was subject to psychogenic faints and/or falls when faced with unpleasant circumstances. Since age 28, she demonstrated frequent brief delusional moods (Wahnspannung) and auditory hallucinations while clearly conscious. She experienced persecutory delusions, believing, for example, that someone in the hospital ward was telling wicked stories about her and had stolen her personal belongings. Her psychotic symptoms have been controlled by haloperidol (1.5 mg/day).
Patient 4 was a Japanese man who died of acute pneumonia at age 47.
Neurological findings. This patient showed mild dysarthria and mild gait ataxia at age 30, both of which were slowly progressive. At age 39, he suffered from neuroleptic malignant syndrome resulting from administration of haloperidol and levomepromazine. He showed generalized tonic-clonic seizures and athetoid movements at age 41. He experienced generalized tonic-clonic status epilepticus repeatedly and became almost bedridden at age 45.
Psychiatric findings. He showed aspontaneity, emotional withdrawal, and muttering starting at age 32. At age 38, he exhibited loss of association and self-mutilation, and was admitted to a psychiatric hospital with a diagnosis of schizophrenia. He developed delusions of persecution and reference in clear consciousness at age 39. He also expressed thoughts that unless he used the toilet frequently, his urine flowed backward and spurted from his mouth. These delusions lasted for 18 months. After these delusions disappeared, emotional instability, aggression, and behavioral disinhibition (sexual aberration) were preponderant. His memory function and daily activity level declined gradually but profoundly.
These four patients with DRPLA exhibited paranoid symptoms while fully conscious, not in delirium. In general, the psychotic aspects of DRPLA have received less attention than the neurological aspects, though some papers8 have described patients with DRPLA presenting psychotic symptoms. Naito et al.7 reported two inpatients clinically diagnosed with schizophrenia who turned out to be suffering from DRPLA. The relative frequency of psychosis we observed among our DRPLA patients was similar to a previously reported frequency of 10%: 5 patients showed certain delusions or hallucinations among 50 DRPLA patients. The prevalence of psychotic phenomena in DRPLA might be higher than expected.
Symptomatically, delusions of persecution and reference were prominent in our patients. These symptoms are very common with psychosis, irrespective of etiology. Furthermore, our patients sometimes exhibited sudden delusional ideas. These psychopathological symptoms closely resembled those of schizophrenia. Thus, psychosis in DRPLA is often difficult to distinguish from schizophrenia on the basis of symptoms alone. Psychotic symptoms emerged prior to overt neurological dysfunction (seizures and truncal ataxia) in some of our patients. Patient 4 was initially treated as schizophrenic by several experienced psychiatrists. There are some reports of patients with DRPLA and psychosis who have been misdiagnosed.7,8 Although dementia is not conspicuous in DRPLA, the changes of personality frequently observed suggest cerebral dysfunction. The delusions often reflect uncontrollable anxiety and emotion regardless of their theme. Patients, because of subtle mental changes, may confuse and misinterpret everyday occurrences. These delusions may often be transient. The psychotic symptoms generally disappeared in our patients in the course of mental deterioration and with low doses of neuroleptics.
Each of our patients showed clinical manifestations that differed from those of other affected individuals in their family. Takahashi et al.5 described the diversity of neurological symptoms in DRPLA. The psychiatric phenomena, too, are diverse. In general, clinical manifestations relate closely to age at onset. Most of the patients presented above exhibited psychosis in middle age (mean 37.8 years). The mother of Patient 2 presented severe depression in her sixties. In contrast, the children of Patients 1 and 2 developed severe epilepsy and learning disabilities. Ikeuchi et al.1 showed that patients with long CAG repeats have an earlier onset, whereas psychosis with full consciousness is found mostly in patients with adult-form DRPLA and comparatively short CAG repeats.
DRPLA has been reported mainly in Japanese populations. The entity appears to be rare in other ethnicities. Burke et al.9 reported a relatively high frequency of an expanded CAG repeat among Japanese. However, the development of genetic testing has allowed diagnosis of patients in Europe and North America. Warner et al.10 suggested that DRPLA is probably more common in non-Japanese populations than is generally thought. Patients with psychosis who show autosomal dominant neurological or psychiatric symptoms may require further examination.
The authors thank Dr. Marcus Wenner for his practical advice.