Authors: Perminder S. Sachdev

Secondary Schizophrenia (87 page)

atric disturbance have been reported; in one, 4 of
87].
A small number of cases have been reported where
35 cases suffered psychiatric disturbance, 3 of these
psychosis was the sole initial manifestation
[71, 84, 86,

being neuroleptic-responsive psychotic disorders
[98].

88, 89].
There have been a limited number of cases
A further series found psychiatric disturbance in 7 of
described where a diagnosis of schizophrenia was
10 CTX patients, predominantly agitation and psy-made, and the patient treated with neuroleptics alone
chosis
[99].
Some of these psychoses developed in
for a number of years, before gait impairment and
the absence of cognitive impairment. Other authors
steep cognitive decline resulted in a diagnostic revi-have reported depression in CTX sufferers
[100, 101],

sion
[71, 85, 86]
. Additionally, we have also described
and more recently a frontotemporal dementia pic-

218

a presentation in adulthood with rapid-cycling bipolar
ture in a compound heterozygote
[102].
Because of
Chapter 16 – Storage disorders and psychosis

the exceptional rarity of CTX and the small number
Whereas some isolated case reports have suggested
of case reports, definitive conclusions are difficult to
that, like NPC, some patients with type II AM may
draw. However, it should be noted that 10 patients
present as, and be diagnosed with, schizophrenia prior
have been reported as suffering psychosis in an illness
to the onset of frank neurological symptomatology
that has perhaps been diagnosed in only 200 patients
[115]
, the most compelling evidence suggestive of a
worldwide
[103].
This suggests that it occurs in up to
greater than expected rate of psychosis in the disor-5% of patients, a rate five to ten times higher than the
der comes from a few small series. Gutschalk and col-base rate of schizophrenia in the population. The early
leagues
[110]
described a trio of siblings, one of whom
axonal dysfunction in CTX may be reflected in a pre-developed a psychosis characterized by delusions and
ponderance toward psychotic (and other psychiatric)
hallucinations after the onset of sensorineural hear-symptoms until gross neuronal loss (and dementia)
ing loss. Malm and colleagues described a series of 45

supervenes, much like that seen in NPC.

patients over the age of 15, and found clearly diag-nosable mental illness in 25%. The majority of these
patients presented with a psychotic disorder charac-

Alpha mannosidosis

terized by delusions, hallucinations, confusion, and a
Alpha mannosidosis (AM) is a recessively inherited
prolonged period of postpsychotic somnolence
[116].

lysosomal storage disorder that results from deficiency
Like the other disorders described in this chapter, psy-of alpha mannosidase in lysosomes
[104].
The illness
chosis in these patients had a distinctly “organic” feel,
is characterized by mild to moderate intellectual dis-being accompanied by cognitive changes as well as
ability, hearing loss, skeletal changes, and recurrent
significant neurological signs at the time of presenta-infections
[105].
Most sufferers develop illness early in
tion. Like NPC, AM seems to initially affect myelinated
childhood (type I) and die of severe infection. A more
structures before progressing to involve the whole neu-indolent form (type II) occurs in a minority of patients
ronaxonal unit, and it may be this initial anatomi-who survive to adulthood
[106].

cal disconnection that predisposes adult individuals to
Alpha-mannosidase is coded by a gene on 19p13.2-psychosis prior to, or coincident with, the onset of their
q12 and functions in the normal lysosomal process-neurological and cognitive impairments.

ing of N-linked oligosaccharides
[107].
A range of
splicing, mis-sense, and nonsense mutations to the
Adult neuronal ceroid lipofuscinosis:

gene have been described, although no clear genotype–
phenotype correlations are evident
[108].
Deficiency of
Kufs’ Disease

alpha-mannosidase results in the intralysosomal accu-The neuronal ceroid lipofuscinoses (NCLs) are a group
mulation of mannose-rich oligosaccharides and the
of neuronal storage disorders, one of which is Batten’s
formation of storage vacuoles in neuronal and glial
Disease – the most common neurodegenerative disor-cells
[105].
This appears to impact significantly upon
der in childhood
[117].
Eight different genetic forms of
myelin formation in animal models and human neu-NCL are thought to exist, although at present only five
ropathological studies
[109].

genes have been discovered
[118].
Most of the defec-In type II AM, the predominant features are cere-tive proteins in the NCLs are associated with lyso-bellar ataxia, hearing loss, neuropsychological impair-somal accumulation of mitochondrial ATP synthase
ment, and retinopathy
[110].
MRI scanning shows
subunit c
[119].
Adult neuronal ceroid lipofuscinosis
periventricular T2-hyperintensities in white matter
(ANCL, Kufs’ Disease), was first described by Kufs in
[110, 111],
which has been suggested as secondary to
1925
[120]
and is thought to result from mutations in
demyelination
[112]
although it is more likely to be an
an as yet undiscovered gene, CLN4
[118].

effect of myelin vacuolation
[113].
Cortical and cere-ANCL is usually inherited recessively
[121],

bellar atrophy is also not uncommon in type II patients
although occasional dominant forms have been
[110, 114].
Diagnosis is established by the combina-described
[122, 123].
Symptoms most commonly
tion of a suggestive urinary pattern of oligosaccharides
appear at the beginning of the fourth decade but
and demonstration of significantly reduced enzyme
may be present early in the second. Neuropsychiatric
activity in leukocytes or cultured skin fibroblasts. The
disturbance in adolescent or adult-onset cases is
only treatment option is bone marrow transplantation
very common
[124]
. Berkovic described two sep-

219

[107].

arate phenotypic groups of ANCL. The first group
Organic Syndromes of Schizophrenia – Section 3

(type A), was characterized clinically by progressive
A model for psychosis secondary to

and treatment-refractory myoclonic epilepsy and
storage disorders: Niemann-Pick type C

dementia. Type B presented with neuropsychiatric
disturbance, facial dyskinesia, and dementia
[124,

As previously described in this book Chapter 6,
125].
The visual signs commonly present in childhood
much can be learned from the understanding of
onset-forms of NCL (known in the nineteenth and
how organic diseases that present with schizophrenia-early twentieth centuries as “amaurotic idiocy”) are
like psychosis produce psychotic symptoms, for this
absent in ANCL
[118].

may inform the biological model and ultimately the
The characteristic neuropathology of ANCL is
treatment of schizophrenia. The core neuropathol-accumulation of lipofuscin-like material in lysosomes
ogy of schizophrenia remains elusive, although it has
in neuronal and extraneuronal tissue, and diagnosis
been seen increasingly as a disorder of connectiv-rests on identification of characteristic inclusions in
ity
[139, 140, 141],
particularly between frontal and
skin punch biopsy or leukocytes
[118].
The distribu-temporal cortical regions and subcortical structures
tion of abnormal lysosomal inclusions in neurons is
[3,
140].
Much evidence points to the role of den-commonly diffuse through cortical and subcortical
dritic and synaptic connections as anatomical sub-neurons, but may be localized to the cerebral cortex
strates of this disconnectivity
[142, 143, 144].
Myeli-in a quarter of cases
[125].
Hippocampal/enterorhinal
nated axon structures are another key carrier of much
cortex may be particularly susceptible
[126].
Unlike
CNS connectivity; hence, pathology in myelinated
most childhood forms, enzyme analysis or DNA test-structures may also play a role
[83,
145, 146].
The
ing is not available, as the presumed CLN4 gene has
lipid-rich nature of myelinated axons, which is depen-not been localized. MRI often shows cerebral and cere-dent on endogenous cholesterol
[147],
renders them
bellar atrophy, callosal thinning, and may show other
highly vulnerable to disturbances of cholesterol or
features such as altered signal in subcortical nuclei,
other lipid metabolism
[55].
Given that disturbances
whereas SPECT commonly shows regional cortical
in lipid biology may play some role in the pathology of
hypoperfusion
[127, 128, 129].

schizophrenia
[148],
an understanding of how myeli-ANCL presents with psychosis in up to 20% of
nated axons are functionally and structurally affected
patients, with ages of onset between 13 and 41
[130,

by NPC may provide a model for understanding how
131, 132, 133, 134, 135, 136, 137].
Backman and col-storage disorder-related psychosis develops in these
leagues, in a series of juvenile NCL patients (mean
disorders.

age 15 years), described five adolescent patients with
Using NPC as a model, its adolescent or early adult-psychotic symptoms warranting psychotropic medi-hood form may potentially disrupt key neurodevel-cation, although affective symptoms (predominantly
opmental processes occurring during this period of
depression) were more common
[138].
Characteris-CNS development, such as frontotemporal myelina-tic psychotic symptoms appear to be auditory hal-tion
[6],
impacting upon frontotemporal connectiv-lucinations, delusions, and thought disorder
[137],

ity and thus leading to psychosis
[3,
140].
The ini-although occasionally catatonic motor changes are
tial cellular impact of NPC appears to occur at the
present
[136].
Neuropsychological impairments are
axonal level, implicating the “macroconnectivity” that
common, often with a mixed subcortical/cortical pic-may underpin functional connectivity in the onset
ture of psychomotor slowing, impaired new learn-of psychotic symptoms in NPC
[83].
Pathology in
ing, and executive and attentional impairments
[135].

the striatum as described could also disrupt frontal-An apparent sensitivity to the motor side effects of
subcortical connectivity, which has also been linked
neuroleptic medication complicates the treatment of
to psychosis in schizophrenia
[149].
The rates of psy-ACNL psychosis, including dystonia
[131, 135]
and
chosis in adult-onset NPC seem to approach those
neuroleptic malignant syndrome
[136].
This sensitiv-of adolescent/adult-onset metachromatic leukodys-ity has been attributed to a combination of subcorti-trophy (MLD), a disorder predominantly affecting
cal neuropathology and potentially muscle membrane
white matter, where up to 50% of cases in this age
pathology
[136].
Treatment of psychosis, notwith-group present with psychosis
[2,
150].
In MLD, psy-standing motor side effects, is usually with neuroleptic
chotic symptoms may be a result of impaired CNS