Secondary Schizophrenia (92 page)

mutation itself
[6, 7].

More than 100 disease-associated point mutations of
mitochondrial DNA have been identified
[8].
The
Mitotic segregation

exact number of identified mitochondrial DNA deletions and nuclear DNA mutations, however, remains
Mitochondrial numbers will vary from cell to cell
unclear. These mutations may impair the respiratory
within and between tissues and at different times
chain or any other mitochondrial processes through
within the development of cells. The division of a
effects on: respiratory chain complex structure, assem-heteroplasmic cell may lead to different amounts of
bly proteins, mitochondrial membranes, mitochon-mutated mitochondrial DNA in the daughter cells.

drial division or intramitochondrial metabolism of
The variations in mitochondrial number will also be
lipids, cholesterol, amino acids, the urea cycle, or
determined by tissue type and the metabolic needs of
apoptosis. Whereas the type of tissues most com-the cells. Mitochondrial DNA replication occurs at a
monly affected are well known, the exact mecha-much greater rate than nuclear DNA replication, is
nisms through which mutations lead to the spectrum
independent of the cell cycle, and is occurring con-of clinical symptoms in any one individual remain
tinuously even in nondividing cells, such as muscle or
unclear.

brain
[2].

Disorders due to mutations in the nuclear genome
tend to have a more consistent clinical pattern and to
Role of autosomal genes on mitochondrial

present at a younger age compared to mitochondrial
genome disorder. A number of these disorders such as
function

Leigh Syndrome, infantile myoclonic epilepsy, mito-As discussed earlier, mitochondrial function is also
chondrial neurogastrointestinal encephalomyopathy
determined by cell nuclei genes. Mitochondrial dis-and Coenzyme Q10 deficiency are associated with
orders can therefore be inherited in a Mendelian
mental retardation, seizures, and either white-matter
pattern, that is, autosomal dominant or recessive
disease or basal ganglia disease. The relatively early
inheritance.

involvement of the central nervous system, the occurrence of seizures, and mental retardation usually lead
Several broad clinical implications follow from the
to a diagnosis in childhood.

previous discussion of genetics
[7]:

Disorders related to mutations in the mitochon-1 Mitochondrial disorders may be sporadic,
drial genome on the other hand often present in
maternally inherited, or inherited in an autosomal
early adulthood and can vary significantly in their
pattern.

clinical phenotype due to heteroplasmy, differential
2 Siblings may show a very broad range of clinical
tissue distribution, and potentially greater environ-variability due to differences in the inheritance of
mental interaction
[9].
It is this latter group that is
230

heteroplasmic mitochondria.

of greatest relevance to the current discussion given
Chapter 17 – Mitochondrial disorders and psychosis

schizophrenia often begins in early adulthood after
Table 17.1
Clinical features of
relatively normal development, can present in a vari-mitochondrial disorders
ety of ways even within the same family, and dis-Exercise intolerance
plays clinical variation during the course of illness. The
Short stature

“consistent” inconsistency of mitochondrial genomic
Ptsosis with progressive ophthalmoplegia

disorders at a genetic and clinical level mirrors what
Sensorineural hearing loss

schizophrenia clinicians and researchers have long
observed, that is, that the presentations and course
Pigmented retinopathy

of illness is consistently inconsistent. In this regard,
Optic atrophy

schizophrenia shares some of the characteristics of
Seizures

mitochondrial disorders:

Basal ganglia lesions

1. Strong genetic heritability

Diabetes

2. Siblings and twins show a wide variability in
Cardiac conduction abnormalities

expression of disease

Cardiomyopathy

3. Within the one individual there will be variability
in the clinical picture over time

of the major features of the mitochondrial disorders
4. Expression of illness is influenced by

will be followed by a review of cases that have been
environmental factors

reported in association with a psychotic illness or
Several lines of investigation point to poten-schizophrenia.

tial mitochondrial involvement in patients with
schizophrenia. A higher rate of maternal transmission
Mitochondrial disorders due to

has been identified in patients with schizophr
enia[10,

mitochondrial genome mutations

11].
Altered mitochondrial gene expression
[12,

13]
and reduced mitochondrial numbers
[14]
have
Diseases caused by mitochondrial oxidative phos-been identified in postmortem studies of brains
phorylation are the commonest inborn errors of
from patients with schizophrenia. In a postmortem
metabolism accounting for 1 in 5,000 live births
[17].

study, Cavelier and colleagues
[13]
identified a 63%

For the reasons outlined above, there is no clear
reduction in cytochrome-c oxidase activity in the
genotype–phenotype relationship, especially for the
caudate nucleus and a 43% reduction of COX in the
mitochondrial genome disorders. The patterns of clin-frontal gyrus compared to control subjects. Patients
ical presentation will vary significantly with regard to
with Alzheimer’s Disease did not exhibit these
age of onset, the temporal order of symptoms and
changes. Martorell and colleagues
[15]
investigated 6

conditions, and the prognosis of the disorders. Clin-mother–child schizophrenia pairs and compared their
ical features common to mitochondrial disorders are
mitochondrial genome to 97 control subjects. They
summarized in
Table 17.1.
The majority of these clin-identified previously unreported mis-sense variants in
ical feature disorders have been described in patients
mother–child pairs that were not seen in the normal
with each of the named mitochondrial syndromes
controls. Two of these mis-sense variants had been
described below. Only those clinical features consid-previously identified in patients with bipolar disorder.

ered to be typical of the various syndromes will be dis-The authors propose these variants that encode
cussed, although “overlap” syndromes have also been
Complex 1 subunits are associated with psychotic
described.

disorders. In contrast to these findings suggestive
of mitochondrial abnormalities in schizophrenia,
Mitochondrial encephalomyopathy,

a study of 300 patients found no one to have the
lactic acidosis, strokelike episodes

mitochondrial mutation that is most common in
MELAS (discussed later)
[16].

syndrome

To further examine the relationship between mito-Mitochondrial encephalomyopathy, lactic acidosis,
chondrial disorders and schizophrenia, a review of
strokelike episodes syndrome (MELAS) is the com-cases of schizophrenia in patients with documented
monest of the mitochondrial disorders and will
231

mitochondrial disorders is warranted. A discussion
usually first present before early adulthood after a
Organic Syndromes of Schizophrenia – Section 3

period of normal development. An A to G substitu-ally abnormal. There is no specific treatment, although
tion at nucleotide 3243 of tRNA leucine (A3243G

appropriate management of the epilepsy is crucial.

tRNALeu(UUR)) is one of the commonest disorders and
accounts for about 80% of MELAS cases
[8].
A fur-

Kearns-Sayre Syndrome

ther 10% of mutations are in other parts of this same
Kearns-Sayre Syndrome (KSS) is a sporadic single
gene, the remaining 10% of mutations occur in 6

mutation disorder characterized by a relatively well-other mitochondrial genes
[5, 7].
Strokelike episodes
recognized triad of progressive external ophthalmo-are the hallmark of MELAS and lead to hemipare-plegia, pigmentary retinopathy, plus one of: heart
sis, hemianopia, and cortical blindness. Vomiting and
block, cerebellar ataxia, or elevated cerebrospinal fluid
migraine-like headaches are often associated clinical
(CSF) protein. Muscle biopsy reveals ragged red fibers
symptoms
[5].
Lactic acid level is elevated and has
and serum lactate is often elevated. MRI will often
been correlated with the level of neurological symp-show diffuse central white-matter abnormalities and
toms
[18].
The course of the disorder is highly variable,
basal ganglia calcification
[7].

ranging from single strokelike episodes through to
combinations of the conditions outlined in
Table 17.1,

although optic atrophy and retinopathy are relatively
Other mitochondrial disorders

rare in MELAS. The diagnosis is based on the clinical
Maternally inherited Leigh syndrome (MILS) is an
syndrome, muscle biopsy showing ragged red fibers,
infantile encephalomyopathy with seizures, dysto-and elevated serum lactic acid levels. Ragged red fibers
nia, heart block, and optic atrophy. Leber hereditary
represent muscle fibers with mitochondrial prolifera-optic neuropathy (LHON) is a maternally inherited
tion, presumably a response to mitochondrial failure,
cause of bilateral visual neuropathy in young adults.

treated with a particular stain.

Although usually confined to the optic nerve, it has
The strokelike episodes result in lesions that do
been described together with white-matter pathol-not conform to vascular territories and are found
ogy
[21]
. “Overlap syndromes” have been described
in tempero-parieto-occipital regions, basal ganglia,
that include features typical of MELAS plus one of
brainstem, and cerebellum. MRI will show strokelike
the other syndromes, for example, LHON/MELAS,
lesions in these regions involving grey and white mat-MELAS/MERRF, or Leigh/MELAS
[17].

ter
[7].
The etiology of these lesions remains unclear
with the two main hypotheses being that the lesions
Mitochondrial disorders and

represent the end result of either vascular damage
schizophrenia-like psychosis

“mitochondrial angiopathy” or cellular damage “mitochondrial cytopathy.” A recent model proposes that
Mitochondrial disorders are rare and the clinical lit-mitochondrial dysfunction in endothelial cells or neu-erature relies largely on case reports or case series.

rons leads to neuronal excitability, which triggers a cas-Psychiatric symptoms are usually embedded within
cade of epileptic activity, angiopathic capillary failure,
a panoply of other somatic symptoms so that case
and neuronal loss
[19].
There is currently no available
reports focused on psychiatric symptoms are rela-treatment for MELAS although antioxidants, respira-tively rare and specific reports regarding psychosis or
tory chain substrates, and cofactors have been trialed
schizophrenia are even less common
[22].
A litera-with varying results
[20].

ture review for “mitochondria or mitochondrial disorders” and “schizophrenia or psychosis” was used as
Myoclonic epilepsy with ragged red

the starting base for a search of cases. Further cases
were identified through the reference lists of identified
fibers

articles. Case reports were included if there was a con-Myoclonic epilepsy with ragged red fibers (MERRF)
firmed diagnosis of a mitochondrial disorder by mus-is most commonly caused by a A8344G tRNAlys
cle biopsy or genetic mutation analysis and if there was
mutation and usually presents before middle adult-sufficient information regarding the psychiatric his-hood. Typically, the disorder begins with photosensi-tory. Fifteen reports and two case series were selected
tive myoclonic seizures and is associated with limb-and grouped into one of five categories:
232

girdle weakness, dementia, and cerebellar ataxia. Mus-1. Mitochondrial disease with a psychotic illness
cle biopsy reveals ragged red fibers and the EEG is usu-suggestive of schizophrenia (10 cases)
Chapter 17 – Mitochondrial disorders and psychosis

2. Mitochondrial disorders with psychiatric