Secondary Schizophrenia (93 page)

Coenzyme Q and idebenone (free radical

symptoms that were related to a delirium or

scavenger drug), which improved his psychiatric
dementia (3 cases)

state. His schizophrenic symptoms disappeared
3. Mitochondrial disorders with a strong family
several months later.

history of schizophrenia (2 cases)

3. A novel mutation was identified in a 27-year-old
4. Wolfram Disease (case series)

man who initially presented with psychotic

5. Other (review series)

symptoms, depression, and suicidal ideas
[27].
He
was noted to have bilateral deafness and cerebellar
signs. MRI revealed cerebral/cerebellar atrophy
Mitochondrial disease with a psychotic

and T2 hyperintensities of the left basal ganglia.

By age 33, he was blind, had severe muscle

illness suggestive of schizophrenia

weakness, ataxia, and cognitive deficits. MRI
1. Mizukami and colleagues have described a patient
abnormalities had progressed and now included
with MELAS in three separate case reports at
periventricular white-matter changes. Muscle
different stages of the man’s illness
[23, 24, 25].

biopsy revealed ragged red fibers and mutational
The final report describes the postmortem

analysis identified a novel heteroplasmic A3274G

findings in this man. He had presented at age 19

tRNALeu(UUR) mutation. The mutation was not

with generalized muscle atrophy and abdominal
identified in any tested maternal family

pain. He developed a medication-responsive

members.

schizophrenic illness, characterized by auditory
4. Amemiya
[28]
describes a man with no family
hallucinations, persecutory delusions, and

history of neurological disease diagnosed with a
disorganized behavior with relapses at the ages of
point mutation C3256T tRNALeu(UUR) gene after
28 and 30. He subsequently developed a

presenting at age 36 with muscle atrophy and
progressive dementia. At age 35, he had a 3-week
weakness. Prior to this, he had had a 7-year
period of akinetic mutism and myoclonus. During
history of episodic psychiatric symptoms such as
this period, he was found to have sensorineural
“delusions and confusion.” The patient continued
hearing loss, hypertrophic cardiomyopathy, and
to have episodic psychiatric symptoms, exhibited
seizures. Over the next 3 years, he displayed
a progressive dementia, myoclonus, ataxia,

disinhibited behavior, transient ischemic attacks,
seizures, ophthalmoplegia, and paralytic ileus.

progressive muscle atrophy, nephrotic syndrome,
Interestingly, the muscle weakness did not

and paralytic ileus. He died of heart failure aged
progress at the same rate as the central nervous
38. Postmortem revealed widespread cortical

system (CNS) symptoms and the authors noted a
infarct-like lesions, cerebral and cerebellar
decline in the proportion of mitochondrial

white-matter gliosis, demyelinating lesions, and
mutation in two muscle biopsies taken at the ages
posterior column and spinocerebellar tract

of 36 and 45. The patient died of heart failure aged
degeneration. Electron microscopy revealed

46. The authors speculate that the proportion of
abnormal mitochondrial aggregates in smooth

mutated mitochondria within a tissue type will
muscle cells and cerebral/cerebellar vascular
influence the severity of illness in that tissue and
endothelium. The authors postulated that the
highlight the different rates of illness progression
pathogenic basis of the lesions was consistent with
in different tissue types within the one individual.

a mitochondrial angiopathy.

5. Inagaki
[29]
describes a 37-year-old man of short
2. Yamazaki and colleagues
[26]
(English abstract
stature and poor school performance who was

only available) reported on a 37-year-old man
diagnosed with sensorineural hearing loss at 29,
with an 8-year history of schizophrenic psychosis
Wolff-Parkinson-White syndrome, and diabetes at
and dementia who developed neuroleptic

31 years of age. At around this time, he developed
malignant syndrome on haloperidol. Physical

auditory hallucinations and persecutory

examination revealed muscle atrophy and

delusions, which resolved within a week of

weakness. Muscle biopsy showed ragged red fibers
treatment with haloperidol. Four years later, in the
and focal cytochrome-c oxidase deficiency.

context of behavioral disturbance, he was further
233

MELAS was diagnosed and he was started on

investigated and a point mutation was identified
Organic Syndromes of Schizophrenia – Section 3

at A3243G tRNALeu(UUR). There was no evidence
the age of 18, she had two strokelike episodes
of muscle atrophy or weakness. A muscle biopsy,
involving the left tempero-parietal and right
electromyography, and MRI scan were all normal.

tempero-occipital regions within several months
The clinical course progressively deteriorated with
of each other and developed focal epileptic

affective blunting, personality change,

seizures. She was also diagnosed with

disinhibition, and abulia. He was admitted and
Wolff-Parkinson White Syndrome and

treated with idebenone with good effect on

retrocochlear deafness. No definitive diagnosis
behavior and affect. The authors describe this as a
was made at this time. At age 22, she developed
case of maternally inherited diabetes and deafness
paranoid delusions, affective instability, and
as opposed to MELAS, given the lack of strokes or
disinhibition, which were treated over the ensuing
myopathy. Both clinical syndromes, however,

years with antipsychotic medication. She was also
arise from the same point mutation.

found to exhibit progressive aphasia and apraxia.

6. Prayson and colleagues present a 47-year-old
The diagnosis of MELAS was made at the age of
woman with MELAS who had presented with a

27 on the basis of the clinical history, ragged red
seizure on the background of a 20-year history of
fibers on muscle biopsy, and the identification of a
schizophrenia, migraine, deafness, and a temporal
A3243G tRNALeu(UUR) point mutation. The

lobe infarct
[30].
Investigations revealed bilateral
patient’s subsequent course was marked by

basal ganglia calcification, a left temporal infarct,
ongoing psychiatric symptoms of psychosis,

and an EEG was reported to show evidence for a
delusions of reference and influence, auditory
diffuse encephalopathy. The patient died 3 months
hallucinations, and suicidal ideation. She required
later of septicemia. The postmortem muscle

secure inpatient care due to the severity of her
biopsy identified ragged red fibers and a partial
psychiatric illness. She died at 31 of putative heart
cytochrome-c oxidase deficiency. The mutational
failure. The authors comment on the presentation
screen identified a A3243G tRNALeu(UUR)

of this patient with a chronic schizophrenia-like
mutation.

illness and the possible contribution of the
7. Spellberg reports on a 36-year-old man
[31]
with a
temporal lobe pathology and the focal

15-year history of psychosis, seizures, and

seizures.

sensorineural hearing loss who had been referred
10. Odawara
[34]
reported a patient with MELAS

for diagnostic clarification. The patient’s mother
who had first presented with diabetes, deafness,
and her twin brother both had a history of

and muscle atrophy at 21. She developed

deafness, diabetes, and seizure. This maternal
schizophrenia at age 23 and her cognitive state
uncle also had a psychiatric history. The patient
declined over the ensuing years. The patient had a
was found to have abnormal gait and muscle

family history in her mother and maternal uncle.

weakness. Genetic analysis revealed A3243G

The diagnosis of MELAS was not made until the
tRNALeu(UUR) mutation and a diagnosis of MELAS

patient was 52 years old.

was made.

8. Saijo
[32]
reports on a man diagnosed with
Although the above ten cases provide variable infor-MELAS who had first presented with seizures,
mation regarding the psychiatric symptoms, there is
paralytic ileus, and muscle atrophy aged 10. At the
a consistent theme of the onset of psychotic symp-age of 19, the patient developed psychosis with
toms (with or without features of mitochondrial dis-auditory and visual hallucinations in association
order) prior to the age of 31. Seven of the ten cases
with high CSF and blood lactic acid levels. He was
had a diagnosis of MELAS whereas in the other three
treated with sodium dichloroacetate and the

cases there was no evidence of strokelike episodes.

hallucinations improved with normalization of
The mean age of the patients at the time of onset of
the lactic acid levels.

their psychotic disorder was 24.7 and the mean delay
9. Thomeer
[33]
reports on a patient with no
in years between the onset of psychosis and the con-personal or family history of neurological or
firmation of a mitochondrial disorder was 12.6 years.

psychiatric disease who was assessed at age 14 for
Despite the presence of physical symptoms that, in ret-

234

short stature, with no abnormalities identified. At
rospect, were features of the mitochondrial disorder,
Chapter 17 – Mitochondrial disorders and psychosis

there was a mean delay of 14.0 years from the first
confirmed on muscle biopsy and an A3243G

physical symptoms (mean age 23.3) until the diagno-tRNALeu(UUR) mutation was identified. The
sis. In three cases (case 4/8/9), there was a large dif-authors comment on this case as displaying
ference between the age of psychosis onset (29/19/22)
unusually prominent deep white-matter

and the first physical manifestation of the disorder
involvement in patients with MELAS.

(36/10/14). In all other cases, the psychiatric and phys-13. The role of coenzyme Q in improving psychiatric
ical presentations occurred within a year’s period.

symptoms was also noted by Shinkai and

Interestingly, the one patient in whom the psychosis
colleagues who described a 48-year-old woman
preceded physical symptoms by many years exhib-who presented with strokelike episodes, followed
ited a novel C3256T tRNALeu(UUR) mutation and the
by behavioral change, cognitive deterioration, and
authors speculated on the different temporal progres-paranoid ideation over the course of several
sion of the patient’s symptoms as a reflection of dif-months. The patient had been diagnosed with
ferential mutation loads in different brain regions.

diabetes at age 40 and hearing loss at age 30. There
Seven of the remaining 8 patients with an identified
were no symptoms or signs of muscle weakness or
mutation possessed the A3243G tRNALeu(UUR) point
atrophy. MRI revealed bilateral tempero-parietal
mutation.

T1 hyperintensities and bilateral caudate

calcification. CSF lactic acid levels were increased.

Her father, mother, and younger sister also had
Mitochondrial disorders with psychiatric

hearing loss. A point mutation was identified at
symptoms that were related to a delirium

A3243G tRNALeu(UUR). The woman was treated

with Coenzyme Q and no antipsychotic

or dementia

medications with improvement in her psychotic
11. Kaido
[35]
describes a 53-year-old Japanese lady
symptoms and reduction of elevated CSF lactic
whose index presentation was with vomiting,

acid levels.

anuresis, and clouded conscious state on a

These cases occurred in older adults who had been pre-background of 6 months of apathy. She had two
viously well. The psychotic presentations occurred in
daughters with known diagnoses of MELAS. All
the presence of what is likely to have been pronounced
three exhibited the A3243G tRNALeu(UUR) point
neurodegenerative disorder and are unlikely to have
mutation. The patient’s mother had been short but
been symptoms characteristic of schizophrenia.