Secondary Schizophrenia (139 page)

uously displaying these movements. The movements
have a stereotyped quality, and in the later stages
may become more athetoid. The patient cannot hold
Psychiatric symptoms

the protruded tongue (impersistence), and this phe-The initial changes are often subtle alterations in per-nomenon is observed in other muscle groups as well.

sonality. Patients are usually described as irritable, sus-The gait may be affected by a curious dance-like
picious, annoying, impulsive, or eccentric. They may
ataxia (choreic dance). The speech becomes dysarthric
become excessively religious or grandiose. Poor self-and explosive. Eye movements are affected in most
control with alcohol abuse and sexual promiscuity
patients, with impaired initiation and slowness of sac-are also described, and rates of criminal behavior are
cades and distractibility of ocular fixation. The muscle
reportedly increased. Other patients become morose
tone is variable. There may be hypotonia, or varying
and apathetic and neglectful of themselves. Personal-degree of rigidity, associated with tremor and bradyki-ity change has been reported in about one-half of HD

nesia. Striate rigidity rather than chorea is an impor-patients. In one recent study using a structured assess-tant feature of some cases of early-onset HD (West-ment
[17]
, a DSM-IV diagnosis of personality disorder
phal variant). In later stages, the diaphragm and bulbar
was present in 10 of 21 (47%) of HD patients (mean
muscles may be involved, resulting in jerky breathing,
age 52.1 years), with the following subtypes: labile,
staccato speech, and dysphagia. After 10 to 15 years,
disinhibited, paranoid and apathetic, as well as a dis-the patient is no longer able to stand or walk and dete-order characterized by child-like regressive behavior.

riorates into a vegetative state.

Twenty percent of the patients with personality disorder did not meet DSM-IV criteria for cognitive disor-Cognitive symptoms
der or dementia. Personality disorder may sometimes
be present for many years before the development of
The early features are a general inefficiency at work
the movement disorder.

and in managing daily routines, with the patient
Affective disorder is also common in HD. In a sur-becoming disorganized and slipshod, suggesting exec-vey by Folstein and colleagues
[18],
41% showed major
utive deficits. Thinking becomes slow and rigid, with
mood disturbance, 32% being depressed and 9% bipo-delayed reaction time and poor working memory
[9].

lar, with the mood disorder predating the motor symp-The patient makes more perseverative errors on the
toms by 2 to 20 years. The mood disorder appeared
Wisconsin Card Sorting Test
[10].
Concentration is
to be confined to certain families, with higher rates
poor and abstraction and judgment are affected. Mem-of mood disorder in the relatives of affected individ-ory is not prominently disturbed, unlike Alzheimer’s
uals. In a recent survey
[17],
major depression was
Disease, although problems have been noted in both
reported in 28%, minor depression in 14%, and mania
declarative and procedural memory
[9, 11, 12].
Lan-in 5%. Suicide was found to account for 7% of deaths in
guage, gnosis, and praxis are usually spared
[12, 13],

nonhospitalized patients
[19]
. Psychosis in HD is dis-at least in the early stages, although word finding dif-cussed later.

ficulties, paraphasias, and decreased speech produc-tion are seen in later stages. Visuospatial functioning
has been less well studied, but deficits were reported
Longitudinal course

in one study in tasks that required the manipulation of
The disease is slowly but relentlessly progressive, with
349

personal space
[14].
The presence of cognitive deficits
the mean duration being 21.4 (range 1.2 to 40.8) in
Organic Syndromes of Schizophrenia – Section 3

one study
[16].
The progression of symptoms is vari-mal range are unstable, with bias toward longer repeats
able, and some patients remain cognitively intact in
in paternal transmission. This results in anticipation
spite of severe motor deficits. The duration is shorter
from father to child, with children developing the disin those with an onset of < 20 years and > 50 years.

ease about 8 years earlier
[28].
Repeat lengths are
Over a 3-year period, the cumulative incidence in non-related to age of onset, explaining about 50%–60% of
symptomatic carriers was 3% if neurological examina-the variance
[29].
Juvenile onset is generally related to
tion was normal, 23% if mildly abnormal, and 60% if
> 60 repeats
[29]
. Genetic modifiers of age of onset
highly abnormal
[20].

have been reported, for example, polymorphism on the
kainite receptor (GluR6) gene for a younger onset
[30]

Diagnosis

and the APOE
∗
4 gene for a later onset
[31].
Lack of
family history may occur in as high as 8% of affected
The diagnosis is strongly suggested by the characteris-individuals. This may be on the basis of new muta-tic clinical features and family history and established
tions, considered to be 1–3%, anticipation, early death
by genetic testing (discussed in a later section). Neu-or misdiagnosis of parent, adoption, or false paternity.

roimaging may play a role in diagnosis and determin-The abnormal CAG repeat sequence leads to a
ing the severity of cerebral involvement. CT and MRI
polyglutamine (polyQ) stretch near the N-terminus
characteristically show dilated ventricles, with frontal
resulting in a mutant Htt. The functions of normal Htt,
atrophy, and particularly atrophy of the heads of the
a 3140 amino acid protein, are incompletely under-caudate nuclei. Significant reduction in the thalamus
stood, but it is highly conserved in evolution and Htt
and the medial temporal structures is also seen
[21].

knockout mice die at 8–10 days of gestation
[32].

The characteristic finding on PET scanning is bilateral
It may have a role in intracellular transport. Mutant
hypometabolism in the caudate and putamen, which
Htt results in toxic gain of function with interference
may be seen in at-risk individuals
[22].
Single pho-with cytoskeletal and vesicular functions and effects on
ton emission computed tomography (SPECT) scan-gene expression leading to apoptosis
[33].
This may be
ning replicates this finding, with reduced blood flow
due to aggregation of the protein or its interaction with
in the caudate
[23]
. Some disorders that may resemble
other proteins. The mutant Htt is expressed through-HD are summarized in
Table 28.1.

out the body. Its levels in the brain are higher in the cor-Given that the genetic abnormality predicts the
tex and the cerebellum than the striatum, but the lat-disease with great accuracy, presymptomatic diagnosis
ter is more vulnerable to the damage. The mechanism
has received much attention and guidelines have been
of degeneration is an important area of investigation if
established [24]. Great care must be taken in ensuring
treatments are to be developed to delay or prevent the
accuracy and laboratories have different practices to
onset of the disease.

ensure this. Preimplantation diagnosis has been suc-cessfully applied [25].

Huntington’s Disease and

Genetics

schizophrenia-like psychosis

Huntington’s Disease is the prototypical autosomal
The association of schizophrenia-like psychosis (SLP)
disease caused by an expanded CAG repeat at the 5

with HD has been reported by many authors and has
end of the hungtingtin (Htt) gene that is located on
been examined from a number of perspectives:
chromosome 4p16.3
[8]
. It is one of a number of trin-

ucleotide repeat neurological disorders listed in Table

28.2. In healthy individuals, the gene carries 6–35 CAG

Epidemiological association

repeats, and no individuals with repeat lengths < 36

The development of suspiciousness and ideas of refer-have been diagnosed to have HD. Repeat lengths > 39

ence is seen in many patients with HD, and these char-definitely result in the disease, with > 98% sensitivity
acteristics have been described as the features of per-and > 99% specificity
[26].
Repeats in the range 36–
sonality change in patients that sometimes predate the
39 are variably penetrant, and the probability of dis-typical features of the disorder by many years. Rates of
ease for 36 or 37 triplets is about 50%
[27].
Repeats
SLP in HD from 5% to 16% have been reported
[34,

350

< 27 triplets are stable during meiosis, whereas 27–
35].
If all psychotic symptoms are included, the rates
35 triplets may rarely expand. Triplets in the abnor-may be as high as 25%
[36].
The symptoms are usually
Chapter 28 – Huntington’s Disease and related disorders

Table 28.1
Disorders in the differential diagnosis of Huntington’s Disease (adapted from [26])
Disorder

Comment

Acquired Disorders

Infections/postinfections

– Sydenham’s chorea

Poststreptococcal in 20% of cases of rheumatic fever
– Neurosyphilitis

Drug-related

– Tardive dyskinesia

Secondary to chronic antipsychotic drug use
– Drug-induced chorea

L-dopa, dopamine agonists, stimulants, antiepileptic drugs, lithium
Basal ganglia lesions

Stroke, tumors, infections, hypoxia

Others

– Senile chorea

Late onset; may resemble late onset HD

– Pregnancy

Rare cause of chorea

– Polycythemia vera

0.5%–5.0% of cases

– Systemic lupus erythematosus

1%–7% of cases

Genetic Disorders

Autosomal dominant

– Spinocerebellar ataxia (SCA)

Chorea may be present in SCA17, SCA2, SCA3 and some othe types; (CAG) in expansion
– Dentatorubral-pallidoluysian atrophy

(CAG) in expansion in atrophin 1; more common in Japan
(DRPLA)

– Benign hereditary chorea

Childhood onset; linkage to chromosome 14q
– Fahr’s Disease

Idiopathic basal ganglia calcification; linkage to chromosome 14q
– Hereditary Creutzfeldt-Jakob Disease

15% of C-J Disease; RP gene mutation in chromosome 20p
– Huntington’s Disease-like 2

Resembles HD clinically and pathologically; CTG expansion Junctophilin-3; African ethnicity
Autosomal recessive

– Wilson’s Disease

Abnormal Cu metabolism; mutation in ATP 7B

– Neuronal ceroid lipofuscinosis (NCL)

Liposomal storage disorder; mutations in 8 different genes (CLN1-CLN8); adult form may be
dominant or recessive

– Pantolthenate kinase-associated

Abnormal Fe accumulaton; 50% of cases form PANK2 mutations
neurodegeneration

Other genetic disorders

– Mitochondrial disorders

Multiple types; maternal inheritance

– Neuro-acanthocytosis

Several conditions:

Choreo-acanthocytosis – recessive mutation in chorein;
McCleod Syndrome – X-linked mutation in Xk gene
Dominant forms

hallucinations and delusions, the latter generally per-as a negative symptom of SLP. In many patients, per-secutory, referential, or grandiose in nature. McHugh
plexity, negativism, and stereotypic movements may
and Folstein
[37]
described the typical evolution of
be seen. It is not uncommon for some patients with
SLP in an HD patient as being preceded by a delusional
HD to have received a diagnosis of schizophrenia, pos-mood from which hallucinations and delusions well
sibly for years, before their accurate diagnosis, a sit-up rather acutely and tend to last many months. Apa-uation more common in the pre-1993 era before the
351

thy is a common feature and may be conceptualized
gene had been identified. The author has encountered a
Organic Syndromes of Schizophrenia – Section 3

Table 28.2
Trinucleotide repeat disorders
Another aspect of the genetics of schizophrenia in
I. Translated (poly Q or polyglutamine)

Triplet

relation to HD is the familial aggregation of the two
triplet repeat disorders

sequence