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213

Section 3

Organic syndromes of schizophrenia: other neurological disorders

Mark Walterfang and Dennis Velakoulis
Facts box

tions of
β
–amyloid, tau, and other proteins can result
r

in neurodegeneration. This chapter restricts its discus-Storage disorders including GM2

sion to specific storage disorders that predispose to
gangliosidosis, Niemann-Pick Disease type C,
psychosis and are due to the disruption to a metabolic
cerebrotendinous xanthomatosis, alpha
pathway that results in the abnormal accumulation of
mannosidosis, and adult neuronal ceroid
one of the key substrates or byproducts of that path-lipofuscinosis all have adult-onset forms.

way.

r
Adult-onset storage disorders present with a
Neuronal storage disorders are a diverse group of
higher than expected rate of psychosis due to
metabolic disorders in which alterations in key path-the presumed interaction between
ways in neuronal metabolism result in the accumula-neuropathology and late neurodevelopment.

tion of a substance, usually a lipid or related molecule,
r
Storage disorders should be suspected in the
which interferes with normal cellular function and
presence of psychosis in individuals with
may ultimately cause neuronal loss. Lysosomes are
movement or other neurological disorders,
intracellular organelles containing enzymes necessary
an atypical course of illness, or a suggestive
for the processing or degradation of proteins, nucleic
family history.

acids, carbohydrates, and lipids. Many neuronal stor-r
Investigations for storage disorders in the
age disorders involve the deficiency of a lysosomal
setting of psychosis are guided by clinical
enzyme, usually a hydrolase, which results in an abnor-features of the illness, and most disorders can
mal accumulation of sphingolipids. Some of these dis-be diagnosed using serum and/or skin biopsy
orders, such as the leukodystrophies, are covered in
testing.

Chapter 18.

r
Substrate reduction therapy is likely to be an
illness-modifying treatment in the future,
Lysosomal storage disorders

although for most disorders antipsychotic
medication is the mainstay of treatment with
A multiplicity of cellular processes occur within lyso-electroconvulsive therapy having anecdotal
somes, where most cellular macromolecules (proteins,
support.

glycoproteins, lipids, and phospholipids) are degraded
by enzymatic “factories,” which then pass out their
monomeric components for reutilization. Impairment

in function of a lysosomal enzyme occurs if it is struc-As already described in previous chapters, neu-turally altered, if alteration occurs to a cofactor pro-ronal assemblies in key circuits can be disrupted to
tein, or if enzyme transport is affected. Each enzyme
produce the characteristic symptoms and signs of
is specific for breaking a particular chemical bond,
a schizophrenia-like psychosis. This disruption can
as opposed to a particular substrate macromolecule.

occur due to a range of perturbations of neuronal func-More than 70 lysosomal enzymes are known, and more
tion, one of which is the accumulation of metabolic or
than 40 disease syndromes involving defective enzyme
other products that may impair key neuronal processes
function have been characterized.

or result in neuronal death. The pathological accumu-Neuronal storage disorders can be broadly broken
lation of cellular products occurs in a range of disor-up into the mucopolysaccharidoses, glycoproteinoses,
214

ders, particularly the dementias in which accumula-sphingolipidoses, other lipid storage disorders, multiple
Chapter 16 – Storage disorders and psychosis

Table 16.1
Lysosomal storage disorders affecting the central nervous system
Lipid storage

Multiple enzyme

Transport

Mucopolysaccharidoses Glycoproteinoses

Sphingolipidoses disorders

defects

disorders

Mucopolysaccharidosis II

Aspartylglycosaminuria

Niemann-Pick

Niemann-Pick

Mucolipidosis type II

Cystinosis

Mucopolysaccharidosis III

Fucosidosis

Disease type A

Disease type C

Mucolipidosis type III

Sialic acid

Mucopolysaccharidosis V

Mannosidosis

Glucocerebrosidase

GM2

storage

Mucopolysaccharidosis VII

Sialidosis

type II

gangliosidosis

disease

Neuroaxonal dystrophy

GM2 gangliosidosis

Metachromatic

leukodystrophy

Globoid cell

leukodystrophy

Table 16.2
Neuronal storage disorders that present with psychosis in adulthood
Altered

enzyme or

Accumulated

Chromosomal

Rate of

Disorder

Eponym

protein

product

Inheritance

location

psychosis

GM2

Tay Sach’s

α
subunit of

GM2 gangliosides

Autosomal recessive

15q23–24

30–50%

gangliosidosis

Disease

β
-hexosaminidase

type I

A

Niemann-Pick

Niemann-Pick

NPC1 or NPC2

Unesterified

Autosomal receissive 18q11–12 or
Up to 40%

Disease type C

Disease type C

cholesterol

14q24.3

Neuronal ceroid

Kuf’s Disease

CLN4

Unknown

Autosomal recessive,

Unknown

Up to 20%

lipofuscinosis

autosomal dominant

Mannosidosis

–

Lysosomal

Undegraded

Autosomal recessive

19p13.2-q12

25%

α
-mannosidase

N-linked

oligosaccharides

Cerebrotendinous

–

Serol-27-hydrolase

Cholestanol

Autosomal recessive

2q35

5–10%,

xanthomatosis

higher rates

reported

enzyme deficiencies, and transport defects
(Table 16.1).

enzyme levels will present in infancy, those with low
Most of these disorders result in significant impair-levels may not present until childhood and those with
ment of early neurodevelopment, producing severe
moderate enzyme levels may not present until adoles-developmental delay or loss of learned skills, and often
cence or early adulthood
[1].
Secondary schizophre-death in infancy or childhood. Because of the early
nia has been associated with the latter group, that is,
age of onset and significant neurological impact, most
those patients with moderate enzyme levels who do
patients do not progress to psychosis. This is primar-not present until adolescence. This pattern of presenta-ily because schizophrenia-like psychosis is a disortion is well characterized in metachromatic leukodys-der of adolescence and early adulthood, and many of
trophy, where psychosis is very common in its adult-these disorders confer a limited lifespan. Addition-onset form (Chapter 18)
[2]
. It is presumed that the
ally, for many affected individuals who enter adult-neuropathological process interacts with the develop-hood, the degree of neuropathology already present in
mental maturity of the CNS during adolescence and
the central nervous system (CNS) may greatly modify
adulthood to produce the key symptoms and signs
the pathoplastic effects of a process that would other-of schizophrenia
[2, 3].
This appears to be the result
wise predispose to psychosis when impacting upon an
of disruptions to, or interactions with, a number of
intact brain. A small number of these disorders, how-key developmental processes, such as synaptic prun-ever, are associated with mutation-driven variations
ing
[4, 5],
myelination of frontotemporal tracts
[6],

in enzyme levels and may present at any stage of the
the development of dopaminergic projections into
human neurodevelopmental lifecycle including adult-frontal GABA-ergic neurons
[7]
and a massive growth
hood
(Table 16.2)
. Whereas patients with little or no
in fronto-limbic connections, particularly from the
215

Organic Syndromes of Schizophrenia – Section 3

amygdala to the cingulate cortex
[8].
Disruptions to
of which may alter neuron-to-neuron microconnec-any of these processes, either through alterations to
tivity. The relationship of ganglioside accumulation
the nature and timing of the processes themselves or
with alterations to neuronal structure, and how it
the integrity of the substrate they affect, may provide
results in neuropathology, remains unclear, although
a neurodevelopmental model for at least some of the
this may occur through direct neurotoxicity
[22],

symptoms of schizophrenia
[3].

altered neuronal electrical properties
[23],
inappropriate apoptosis
[23, 24],
or a CNS inflammatory response
GM2 gangliosidosis type I:

[25].

The neurological presentation of late-onset TSD

Tay-Sachs Disease

is quite variable, and no distinct phenotype–genotype
Tay-Sachs Disease (TSD) was first described by Sachs
correlations exist
[26].
Speech disorder, gait distur-in 1887

[9, 10]
and is an autosomal recessive lipid
bance, and tremor are the most common presenta-storage disorder caused by the accumulation of GM2-tions
[27].
Many patients have normal or near-normal
gangliosides within neurons due to a deficiency in
cognitive function
[27]
, although subtle deficits in
β
–hexosaminidase A
(HEX-A)[11].
In its classic, or
executive function, information processing speed, and
infantile, form, TSD is a rapidly progressive illness
memory may be present in up to half of patients
[28,

characterized by developmental retardation, paralysis,
29].
In a number of patients, these deficits progress in
and blindness and usually results in death by the third
concert with their neurological symptoms
[29].
Neu-year of life
[10]
. The characteristic “cherry red spot” on
roimaging findings in TSD describe cerebellar atrophy
the fundus of an affected infant was first described by
in most patients
[19, 29,
30],
although cerebral atro-Tay, who shares the eponym of this disease
[12].
The
phy may be present in up to a quarter of patients
[29].

juvenile form generally presents by the fifth year, with
Diagnosis generally rests on demonstration of defi-weakness, seizures dysarthria, dysmetria, and death by
cient hexosaminidase activity. Treatment options are
the mid-teens
[13]
. More recently, a late-onset form
limited to bone marrow transplantation
[31],
although
of TSD has been described where psychiatric symp-substrate reduction therapy – potentially a promising
toms may co-present with or predate the develop-short-term treatment for all lipid storage disorders –
ment of neurological disturbances in early adulthood
with miglustat, has shown promise in animal models
[14].

[25].

HEX-A is composed of
α
and
β
subunits, and
Neuropsychiatric presentations occur in up to half
the related enzyme HEX-B is composed of
β
-subunits
of late-onset TSD patients described in unselected
alone. The
α
–subunit gene is located on chromosome
series, and the predominant neuropsychiatric presen-