Secondary Schizophrenia (96 page)

tomatology.

r
Psychiatric illness in patients with

In this chapter, we review the major inherited
leukodystrophies may be indistinguishable

leukodystrophies, with attention to the psychiatric
from primary psychiatric disorders.

manifestations associated with each. The age of
r
Individuals with later-onset forms of

onset and ensuing clinical course with most of
inherited metabolic disorders are more likely
these disorders reflect the severity of the underlying
to develop – and may present solely with –
metabolic defects. Cases that begin in infancy or early
psychiatric illness.

childhood typically run an aggressive course, with
r
The diagnosis of an inherited leukodystrophy
a host of systemic and neurological problems that
should be considered in patients with

make it difficult to discern the associated psychiatric
psychiatric illness and concurrent seizures or
symptoms that might be present. Adult-onset cases,
cognitive decline.

however, follow a more protracted clinical course,
r

allowing the neuropsychiatric consequences of the
Individuals with psychiatric illness and an

white-matter pathology to become manifest. These
underlying inherited metabolic disorder are

adult cases, by potentially allowing phenotype–
often treatment resistant.

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genotype and clinical–pathological correlations, offer
Failure to diagnose an inherited metabolic

insight into the pathology of psychiatric disease. It
disorder can impede treatment and have fatal
is on these adult-onset forms that we focus in this
consequences for certain patients.

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review.

Use of psychotropic medications in patients

with inherited metabolic disorders has the

potential to worsen the underlying disease

Metachromatic leukodystrophy

process and produce serious side effects.

Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder associated with a deficiency of
the lysosomal enzyme, aryl sulfatase A (ASA). MLD

The term leukodystrophy refers to diseases of the white
ing to age of onset and severity of clinical progression
matter, which results in a functional “disconnection”

[1]
. As is the case with many inherited metabolic dis-between parts of the nervous system that communicate
orders, the early-onset cases tend to be associated with
through the affected white-matter tracts. The clinical
an aggressive course of illness and early death. The late-consequences of this “disconnection” depend on the
onset form, however, follows a more protracted clin-localization of the white-matter pathology, whether it
ical course and is often associated with neuropsychi-is in the brain, spinal cord, or brain stem. What are the
atric symptomatology. Indeed, it has been suggested
principal clinical consequences of lesions that inter-that late-onset MLD might serve as a window on the
rupt the white-matter bundles involved in cortico–
underlying pathobiology of schizophrenia
[2, 3].

241

Organic Syndromes of Schizophrenia – Section 3

Genetics and pathobiology

Clinical features and neuroimaging

The gene responsible for MLD has been localized to the
A review of the English literature revealed 81 cases of
long arm of chromosome 22 and a range of mutations
late-onset MLD that provided some information about
has been identified. Some encode inactive ASA (the so-clinical findings
[8, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,

called “O-alleles”) and others encode ASA with resid-

23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37,

ual enzyme activity (“R-alleles”). In general, the O-

38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,

alleles are associated with the severe early-onset forms
53].
The clinical profile that emerges from these cases
of MLD, whereas the R-alleles tend to produce the less
is described in this section.

aggressive late-onset cases
[4].

In all subtypes of MLD, the ASA deficiency leads
Age of onset and course of illness

to impaired conversion of sulfatides to cerebrosides,
The approximate age of illness onset was 25.4 (SD
=

resulting in sulfatide accumulation in tissues. The
11.04 years, range 10–62 years). Neurological symp-principal targets of this process are the myelinated
toms typically presented 4.1
±
7.0 years after the devel-axons of the central and peripheral nervous systems,
opment of psychiatric symptomatology. In 23 cases
the kidneys, and the gall bladder
[1].
When stained
that were followed until death, the duration of illness
with cresyl violet, the affected tissues turn brown, pro-varied from 2 to 47 years with an average of 12.0 (SD
=

ducing the “metachromatic” effect for which the dis-11.8) years.

ease is named.

The late-onset form of MLD is associated with two
Psychiatric features

major phenotypic presentations: one in which the ini-The prevalence of psychiatric illness in patients with
tial symptoms are related to sensorimotor problems
adult-onset MLD is estimated to be high and psychosis
and another that begins with neuropsychiatric distur-has been reported in 53% of published cases, although
bances. A recent study found that these phenotypic
the possible presence of PD was not addressed. Of the
subtypes tend to be associated with specific genetic
81 cases we found in the English literature
[8, 13, 14,

profiles
[5].
Of particular interest is the observation
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30,

that patients who are heterozygous for the I179S muta-

31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,

tion almost invariably present with social and behav-

47, 48, 49, 50, 51, 52, 53],
65 (80%) experienced some
ioral abnormalities that closely resemble those associ-form of psychiatric symptomatology, 29 (36%) devel-ated with schizophrenia.

oped psychosis, and 19 (23%) were diagnosed with
schizophrenia. In many cases, the disinhibition, emotional lability, apathy, silliness, poor judgment, lack
Prevalence

of insight, impulsivity, and perseveration were highly
Adult or late-onset MLD is estimated to affect 1 in
suggestive of a frontal lobe syndrome. It was difficult to
40,000 individuals
[6, 7]
, although this is almost cer-discern the role of impaired cognition in the early pre-tainly an underestimation given that psychiatric dis-sentation. Of note, 66% of adult-onset MLD patients
turbances
[1, 2, 8, 9, 10]
often occur before neuro-eventually suffered cognitive decline, often resulting in
logical features develop. Affected patients tend to be
profound dementia in the later stages of the illness.

diagnosed according to traditional psychiatric categories and the later emergence of significant cogni-

Neurological features

tive impairment or neurological features may be over-Gait disturbance is the most common early neurologi-looked or misdiagnosed.

cal problem in late-onset MLD, followed by dysarthria,
There has been no large-scale study of the preva-seizures, incontinence, and evidence of upper or lower
lence of MLD in psychiatric populations and the
motor neuron involvement. Cranial nerves are usually
results from smaller studies have been compromised
normal. Optic atrophy can occur and in the late stages,
by the failure to test for pseudodeficiency (PD)
[11,

most patients are mute, blind, and unresponsive.

12].
In this state, clinically normal subjects have low
ASA activity but not the genetic defect associated with
Neuroimaging

MLD. PD can be identified through genetic analysis or
MRI reveals diffuse, symmetric, and confluent
242

by the absence of sulfatide excretion in the urine.

demyelination, which preferentially affects the frontal
Chapter 18 – Psychosis associated with leukodystrophies

white matter and corpus callosum while sparing
boys, leading to death before the age of 10. As with
arcuate U fibers
[54]
. As the disease progresses, there
MLD, however, there are now recognized to be less
is significant enlargement of the ventricles due to the
severe forms of the illness, with onset in adolescence or
extensive loss of white matter. Grey matter is typically
even adulthood. It is these later or “adult-onset” forms
only minimally affected and the brain stem and
of ALD that concern us here.

cerebellum are rarely involved. Advances in imaging
technology such as diffusion tensor imaging (DTI)
and tractography
[55, 56]
hold promise for more
Genetics and pathobiology

precisely delineating the disease process.

The ALD gene has been mapped to the q28 region of
the X chromosome. It codes for a protein that has been
Investigations

localized to the peroxisomal membrane
[69, 70]
and
is a member of the ABC (adenosine triphospate bind-

Making the diagnosis

ing cassette) transporter superfamily
[71].
This trans-1. Determination of ASA activity can be carried out
porter forms a “pathway” through which the enzyme
in leukocytes or cultured skin fibroblasts. A
VLCFA CoA synthetase moves from the cytosol into
finding of low enzyme activity is not sufficient to
the intraperoxisomal membrane space
[68, 70].
Muta-confirm the diagnosis as low enzyme activity can
tions of the ALD gene alter the transporter, thereby
also be found in the more common condition of
impairing the ability of the peroxisome to catabo-PD.

lize VLCFAs. Three classes of tissue are preferentially
2. Urine test for sulphatide excretion.

targeted: (1) myelin-producing cells of the CNS and
3. Genetic analysis for MLD gene mutations is
PNS leading to demyelination, (2) the adrenal cortex,
specific and confirmatory for MLD.

resulting in adrenal insufficiency (Addison’s Disease),
and (3) the Leydig cells of the testes, producing hypog-onadism.

Treatment

This pattern of pathology can bring about psy-Currently, there is no treatment that will stop or slow
chiatric symptomatology in two ways. The first is
the progression of MLD. Enzyme replacement therapy,
through central demyelination, which disrupts or “dis-although successful in vitro, was not successful in the
connects” cortical circuits that subserve normal cog-two patients in whom it was attempted
[57, 58, 59].

nitive and emotional function. The second is through
Despite transiently high levels of arylsulphatase activ-adrenal insufficiency, which can lead to impaired
ity in the liver in both cases, there were no comparable
cerebral function and, in severe cases, produce out-increases in the brain
[58].
Bone marrow transplanta-right psychosis, so-called “Addison’s encephalopathy”

tion (BMT) has been carried out on several patients
[72].

with generally poor results to date
[60, 61, 62, 63].
The
Although ALD was long thought to affect only
rationale for this approach is based on the presump-males, the discovery of X inactivation has focused
tion that enzymes, delivered by healthy cells to defi-attention on female “carriers.” This process, by which
cient cells, can be endocytosed and made available for
one of the two X chromosomes becomes condensed
processing the accumulated sulphatides. Additional
and permanently inactive, occurs at random in the
treatments currently being studied include retroviral
embryonic stage. If the defective allele is on the chro-gene therapy
[64],
immunomodulation
[65],
and the
mosome that has been inactivated, there will be no
use of thiol proteinase inhibitors to prevent the break-phenotypic manifestation of the disease. If, on the
down of available arylsulfatase
[66].

other hand, the defective allele is on the active X chromosome, the other having been inactivated, there can
be clinical expression of the disorder
[73].
As many
Adrenoleukodystrophy

as 20% to 50% of female heterozygotes have neuro-Adrenoleukodystrophy (ALD) is an Xlinked disorder
logical signs and symptoms that resemble, and may
in which very-long-chain fatty acids (VLCFA), defined
be diagnosed as, multiple sclerosis
[74, 75].
Only 3%,
as those having greater than 22 carbon chains, accu-however, have cognitive decline and less than 1% of
mulate as a result of defective beta-oxidation within
female carriers have evidence of adrenal insufficiency
243