Secondary Schizophrenia (94 page)

otherwise no medical history was provided.

Medical management improved her medical

Mitochondrial disorders with a family

condition but she developed a “psychosis”

(shouting loudly, fearful hallucinations, and
history of schizophrenia

neuroleptic treatment) and died 4 months later.

14. Campos and colleagues
[37]
report on a Spanish
This is more likely to have been a delirium rather
family with the mtDNA tRNALeu(UUR) 3303 > T

than a psychotic illness.

mutation. The index case was a 6-year-old girl
12. A 58-year-old woman
[36]
presented with
who presented with cardiomyopathy and

cardiomyopathy and muscle weakness, initially in
myopathy. Muscle biopsy confirmed the presence
the upper limbs and rapidly progressing to the
of ragged red fibers and revealed defects in
lower limbs. There was no family history of note.

respiratory chain complexes I and IV.

During the admission, she developed psychotic
Investigation of the family identified that her
symptoms in the form of paranoia, agitation, and
mother, a maternal aunt, maternal grandmother,
hallucinations and was found to have widespread
maternal great grandmother, and a maternal

cognitive deficits across memory, language, and
great-uncle had all suffered with psychiatric
executive functioning. MRI revealed deep

illness from early adult life. The features of the
white-matter hyperintensities in a watershed
psychoses are not described for all family

distribution and bilateral cerebellar white matter.

members but were very similar to those noted in
These abnormalities had not been present on an
the mother and maternal aunt. These included
earlier MRI scan. A diagnosis of MELAS was

recurrent depressive episodes (mother), recurrent
235

Organic Syndromes of Schizophrenia – Section 3

manic-depressive episodes (maternal aunt), and
trophy, and Niemann-Pick Disease type C, each of
psychotic episodes (mother and maternal aunt)
which show rates of psychosis in the 25% range
[43].

since adolescence. It was known that the maternal
grandmother had died of unknown cause aged 68

Other cases

and the maternal great grandmother had died of
Fattal
[22]
has recently reviewed the relationship
early dementia aged 60. None of the maternal
between mitochondrial disorders and a broad range
relatives of the index case had been known to have
of psychiatric disorders. This review identified 19

cardiac or muscle disease. Mutation analyses
case reports of psychiatric disorder in patients with
identified 95% mutant molecules in the proband’s
mitochondrial disorders, nine of which had a psy-muscle and 75% mutant molecules in her blood
chotic illness. These cases overlapped with seven of the
cells. The maternal and maternal aunt’s blood cells
cases presented above (Cases 3–5, 7–10). The authors
contained 25% and 20% mutant molecules,

emphasize the importance of “red flag” physical signs
respectively.

such as muscle weakness and hearing loss in patients
15. Ueda
[38]
identified a 12-year-old boy with asym-with atypical psychiatric presentations. The presence
ptomatic proteinuria who was found to carry a
of seizures, short stature, diabetes, Wolff-Parkinson-point mutation in the tRNALeu(UUR) gene renal,
White Syndrome, or migraines should alert clinicians
but not muscle tissue. The boy was otherwise
to the possibility of mitochondrial disorders in their
healthy. The boy’s mother had depression and
patients.

epilepsy, two maternal aunts had schizophrenia or
amyotrophic lateral sclerosis, and a maternal
grandmother had diabetes. The family members
Conclusions

did not consent to mutation analyses. There was
In the absence of evidence regarding the number of
no history of cardiac disease or myopathy in the
patients with mitochondrial disorders who do not
family.

have schizophrenia, it is problematic to draw causal
conclusions from a case report literature regarding the relationship between these disorders – one
Wolfram Disease

exceedingly rare and the other uncommon. The case
Wolfram Disease is an autosomal recessive disorder
report approach provides important information for
caused by a mutation in the WFDS1 (wolframin) gene
clinicians who care for patients with mitochondrial
on the short arm of chromosome 4
[39, 40].
WFDS1

disorders and those who care for patients with
gene codes for a transmembrane protein found in
schizophrenia. There are also some potential clues for
the endoplasmic reticulum, whose function remains
schizophrenia researchers.

unclear. Wolfram disorder is also known as DID-From a clinical perspective, a survey of patients
MOAD, an acronym for the characteristic conditions
with chronic schizophrenia would quickly detect a
that comprise the disease (Diabetes Insipidus, Dia-wide range of medical comorbidities. It is well estab-betes Mellitus, Optic Atrophy, Deafness). The disease
lished that the prevalence of diabetes, heart disease,
has been associated with multiple mitochondrial dele-cardiac arrhythmias, and poor exercise tolerance is
tions in some but not all families with the disease
[41].

higher in patients with schizophrenia than the gen-A study of 68 homozygous patients revealed very high
eral population
[44].
As pointed out by Fattal
[22],

rates of psychiatric illness
[42].
Forty-one of the 68

these case reports alert the clinician to the possibility
patients had had psychiatric symptoms and 17 (25%)
that his/her patient with a well-defined schizophrenic
were classified as showing severe mental illness. Eleven
illness or a schizophrenia-like psychosis, diabetes,
(16%) patients had a history of psychotic symptoms.

and cardiac disease, who has a stroke, an unex-Further assessment of heterozygous family members
plained seizure, or deafness, may have an undiag-revealed a high rate of psychiatric illness, approxi-nosed mitochondrial disorder. The diagnosis will carry
mately eight times greater than for noncarriers of the
important implications for the patient’s management
Wolframin gene. The high rate of schizophrenia-like
and treatment and highlights the importance of a
psychosis in this disorder is similar to that seen in
clinical understanding of the “secondary schizophre-some other adult-onset neurological disorders such as
nias.” A good understanding of disorders that cause
236

velocardiofacial syndrome, metachromatic leukodys-schizophrenia-like psychosis allow for the recognition
Chapter 17 – Mitochondrial disorders and psychosis

Table 17.2
Mitochondrial disorders with psychotic symptoms: discrepancy between ages of onset of physical and psychotic symptoms
and diagnosis
Delay between onset

Onset (years)

and diagnosis

Case no.

Author

Mutation

Physical

Psychosis

Diagnosis

Psychosis

Physical

1

Mizukami [23]

A3243G tRNALeu(UUR)

19

19

35

16

16

2

Yamazaki [26]

N/A

29

29

37

8

8

3

Jaksch [27]

A3274G tRNALeu(UUR)

27

27

33

6

6

4

Amemiya [28]

C3256T tRNALeu(UUR)

36

29

36

7

0

5

Inagakai [29]

A3243G tRNALeu(UUR)

29

31

35

4

6

6

Prayson [30]

A3243G tRNALeu(UUR)

27

27

47

20

20

7

Spellberg [31]

A3243G tRNALeu(UUR)

21

21

36

15

15

8

Saijo [32]

n/a

10

19

35

16

25

9

Thomeer [33]

A3243G tRNALeu(UUR)

14

22

27

5

13

10

Odawara [34]

n/a

21

23

52

29

31

Mean (yrs)

23.3

24.7

37.3

12.6

14.0

of core symptoms or signs that fall outside those
may be more important than the pathology of the ill-that are usually associated with schizophrenia and
ness itself in predicting major mental illness. Further-that represent either an unassociated separate illness
more, the subtle illness effects seen in neuropatholog-or a marker of a single underlying illness causing
ical and neuroimaging studies in schizophrenia would
both psychotic and other physical symptoms. The
predict that schizophrenia-like psychosis would occur
apparently high prevalence of psychiatric disorders in
early rather than late in a developing neurodegener-patients with mitochondrial disorders similarly alerts
ative disorder and be later supervened by more gross
these patients’ physicians to the need to be aware
clinical syndromes (such as seizures, dementia, and
of psychiatric symptoms and to appropriately man-movement disorder) as the illness load on the CNS

age them as they may be significantly disabling for
progresses. As seen in
Table 17.2,
in the mitochon-patients and families – and may also confer signifi-drial disorders associated with schizophrenia-like psy-cant risk. Psychoses will generally respond to antipsy-chosis, a psychotic illness is often the harbinger of later
chotic treatment regardless of the etiology of the
physical and neurological illness, often by more than a
symptoms.

decade.

The observation that schizophrenia-like psychoses
The role of oxidative stress in schizophrenia has
occur early in the course of subsequently identified
been the subject of several reviews, research stud-neurodegenerative disorders is well recognized and
ies, and the basis for treatment of schizophrenia
may provide important information regarding the
with antioxidants
[45].
Failure of the mitochondrial
brain’s response to insult, whether metabolic, infec-OXPHOS system allows the build up of intracellular
tious, or neurodegenerative, at different stages of its
reactive oxygen species, which can then trigger cell
development (Chapter 16). Neurological disorders,
necrosis and apoptosis. Recent therapeutic efforts in
particularly storage disorders such as the leukodystro-neurodegenerative disorders such as Alzheimer’s Dis-phies, that present in late adolescence and early adult-ease have been targeted at the development of mito-hood tend to present with major psychiatric disorders
chondrially active antioxidants
[46].
A disturbance of
such as schizophrenia, mania, or major depression.

mitochondrial function could account for some of
The wide range of pathoplastic effects of these disor-the most puzzling features of schizophrenia such as
ders and affected regions suggests that the underlying
the nature of its heredity, the phenotypic variation of
developmental maturity of the CNS (and the neurode-illness within individuals over time and between
237

velopmental trajectories that are interrupted by illness)
family members, the high prevalence of medical
Organic Syndromes of Schizophrenia – Section 3

comorbidities, and the potential therapeutic role of
the development of psychosis in individuals who carry
antioxidants. The findings of mitochondrial distur-other biological vulnerabilities for psychosis, such
bance in some schizophrenia sufferers and of an ele-as environmental insult or schizophrenia vulnerabil-vated rate of psychosis in mitochondrial disorders,
ity genes. An interaction of this nature may also
in the absence of clear evidence from linkage studies
explain the elevated rates of psychosis in some mito-that mitochondrial genes are affected in schizophre-chondrial disorders, with those individuals developing
nia pedigrees, raises the possibility that mitochon-schizophrenia-like psychosis possibly being those who
drial function may act as an additional diathesis to
carry other psychotogenic diatheses.