Secondary Schizophrenia (133 page)

GAA expansion.

With time, weakness and wasting develop in the
D ürr et al., 1996 Harding, 1981

muscles of the feet, lower legs, and hands, resulting
(n
=
140)

(n
=
115)

in deformities. Loss of reflexes in the lower limbs is
Clinical Feature

%

%

common, with knee jerks being present in only 1%
[2]

Age (mean
±
SD) year

31
±
13

–

and 12%
[4]
of cases in two series. There is gradual
Age of onset (mean
±
SD)
15.5
±
8

10.5

loss of sensation, vibration, and position sense in the
Neurological Feature

extremities. The plantar response is up-going, suggesting pyramidal tract involvement. The Romberg sign is
Gait ataxia

100

–

usually positive. Dysarthria is common and horizon-Limb ataxia
99

99

tal nystagmus may be present, consistent with cerebel-Lower limb areflexia
87

99

lar and spinocerebellar involvement. Sphincter distur-knee jerk present
12

0.9

bance and swallowing difficulties are absent until late
Loss of vibration sense

78

73

in the disease. Decreased visual acuity and hearing loss
Extensor plantar response

79

89

are also late features.

Kyphoscoliosis and pes cavus may be early signs
Dysarthria

91

97

and are common. Other deformities include flexion of
Horizontal nystagmus

40

20

the toes, hammertoes, or foot inversion.

Muscle weakness in lower

67

88

limbs

Other features

Muscle wasting

lower limbs

39

39

Cardiac involvement was evident on electrocardiography in 67% in the Dürr and colleagues
[4]
series. This
upper limbs

25

49

includes cardiomyopathy of the hypertrophic nonob-Saccadic pursuit eye
30

12

structive type, myocardial fibrosis, and cardiac fail-movement
ure. Patients develop symptoms such as chest pain,
Sphincter disturbance

23

–

shortness of breath, and heart palpitations. About 30%

Swallowing difficulty

27

–

develop impaired glucose tolerance and 10% diabetes
Reduced visual activity

13

18

mellitus. Less common features are facial dysmorphia,
Hearing loss

13

8

seizures, dystonic postures, myoclonus, and postural
Axonal neuropathy

98 (n
=
63)

96

tremor that may not have a causal link with the genetic
abnormality.

Abnormal brainstem ERPs

61 (n
=
29)

–

Abnormal visual ERPs

34 (n
=
34)

–

Psychiatric features

Musculoskeletal

These have been variably reported. Although Friedre-Scoliosis
60

79

ich
[1]
did not report intellectual impairment in his
Pes Cavus

55

55

cases, early reports noted the presence of intellectual
Other Features

impairment in about a quarter of cases in one series
[5]

Cardiomyopathy

63(on ECG)

–

and 15% in another
[6],
which varied in degree from
Diabetes or abnormal

32

10

mild to severe. This high prevalence was not supported
glucose tolerance

by Davies
[7],
who did not find an excess of mental
Facial dysmorphia

3.6

retardation in FDRA, although some patients showed
Seizures

1.4

impairments in recent memory, attention, and concen-Dystonia
1.4

tration. Davies concluded that these patients had mild
but significant cognitive deficits that set in early but
Myoclonus

3.6

were nonprogressive. Dürr and colleagues
[4]
reached
Postural Tremor

1.4

a somewhat similar conclusion that mental retarda-Mental Retardation
3.6

tion was uncommon (5/140
=
3.6% in their series) and
333

∗
Adapted from Dürr
et al.
(1996).

probably not a feature of the disease.

Organic Syndromes of Schizophrenia – Section 3

Personality abnormalities have also been reported,
now known to code for the protein frataxin. The
but the specificity of these is doubted. Irritability, anti-causative mutation is an unstable expansion of a GAA
sociality, episodes of mute or resentful behavior, denial
repeat in the first intron
[13].
The vast majority of
of illness, and excessive preoccupation with religion or
sufferers are homozygous for the GAA repeat, but
mysticism have all been reported
[7, 8].
The relative
compound heterozygotes have been described
[13].

contribution of neurologic deficits and environmental
The number of expansions varies considerably, within
factors in this is unclear. The presence of psychosis is
patients as well as families. In the Dürr and col-discussed later.

leagues
[4]
study, the number of repeats varied from
120 to 1,700. The size of the expansion correlated
Late-onset FRDA

with the age of onset and rate of progression of the
This is defined as onset after 25 years, and the disease
disease
[4],
with smaller expansions leading to later
in these cases is milder overall. Gait and limb ataxia
onset (>25 years) and slower progression, often with
are present in all cases; dysarthria, loss of posterior col-atypical features such as retained tendon reflexes or
umn sensations, and abnormal eye movements are also
hyperreflexia.

common
[4, 9].
These patients are more likely to have
GAA expansion leads to the formation of a

lower limb spasticity and retained reflexes. Cardiomy-

“sticky” triplex DNA structure causing reduced levels
opathy is usually absent
[9].

of frataxin, a protein that localizes in mitochondrial
membranes and crests
[14].
Studies in yeast as well
Laboratory investigations

as animal models have shown that this low frataxin
levels lead to intramitochondrial iron accumulation
Electrocardiography shows features of cardiomyopa-and impaired mitochondrial oxidative phosphoryla-thy, with T-wave inversion, hypertrophy of the inter-tion, contributing to increased oxidative stress and cel-ventricular septum and the left ventricular wall, and
lular damage
[15]
. However, the precise function of
heart rhythm abnormalities, such as tachycardia and
frataxin remains unknown.

heart block. Axonal neuropathy of predominantly sensory type is evident on nerve conduction studies in
many patients. There is often abnormal central motor
Psychosis in FRDA

conduction velocity. Visual and brainstem auditory
A number of case reports of psychosis in FRDA have
evoked potentials may be abnormal. Glucose tolerance
appeared in the literature, but the anecdotes are too few
is impaired in a proportion of cases
(Table 26.1).
MRI
to come to any firm opinion on a specific relationship
shows that atrophy of the cervical cord, atrophy of the
between the two. One of the earliest case reports was by
cerebellum, in particular the vermis, is not uncommon
Davies in 1949
[8],
who reported the case of a 15-year-

[9, 10, 11].
Mild generalized cerebral atrophy may be
old boy who developed motor symptoms at the age of
seen in some cases
[12].
Genetic testing is diagnostic
13 years and became irritable, aggressive toward his
of the disease (discussed later).

parents, developed persecutory ideas and visual hallucinations, and had episodes of rage. His EEG showed
Course of illness

abnormality over the right temporo-occipital region.

In most cases, the disease is slowly progressive, with
Davison and Bagley
[16]
reviewed the evidence for
the person being confined to a wheelchair in 10–15

a “Friedreich’s psychosis” in 1969 and concluded few
years (range 1–25 years) after onset. There are indi-cases existed and the etiology was possibly heteroge-vidual variations, however, and cases occur with long
neous, thereby not supporting a special relationship.

stationary periods or very slow progression. Death
Sporadic reports have continued to appear. Salben-often occurs within 20 years of onset, often from heart
blatt and colleagues
[17]
reported a 36-year-old man
disease, but some sufferers live into their 60s and
who had a gradual onset of persecutory delusions and
70s.

auditory and visual hallucinations in the later stages
of his illness. He died 6 weeks after the initiation of
antipsychotic medication. A more recent report in a
Genetic abnormality

37-year-old female emphasized delusions of reference
FDRA is an autosomal recessive disorder with a
as the major symptoms of psychosis
[18].
Such reports
334

genetic defect mapped to chromosome 9 in the region
are insufficient to extrapolate from FRDA to the
Chapter 26 – Friedreich’s Ataxia and schizophrenia-like psychosis

pathogenesis of schizophrenia, although some specu-of the successful use of risperidone 2 mg/day
[17]
and
lation in this regard has been published
[19].

aripiprazole 10 mg/day
[18]
attest to the benefit of
these drugs in controlling psychotic symptoms. Long-

Treatment

term use of these drugs has not been reported in the
literature.

The treatment of FRDA has until recently been mainly
symptomatic. Considering the likely role of oxida-

Other autosomal recessive

tive stress in the pathogenesis, antioxidants have been
tried. A four-year open study of a combination of coen-

cerebellar ataxias

zyme Q10 and vitamin E reported improvement in
FRDA is one of a group of hereditary ataxias recently
cardiac function and stabilization or slowed decline
reviewed by Fogel and Perlman
[24]
that are autosomal
in neurological symptoms
[20].
A synthetic analogue
recessive and involve spinocebellar degeneration. The
of coenzyme Q10 has been shown to show reduc-

clinical features include cerebellar syndeoms, senso-tion in cardiac hypertrophy but was not found to
rimotor neuropathy, eye signs, movement abnormal-help neurological symptoms of the disease
[21, 22].

ities, seizures, skeletal abnormalities, and skin disorA novel approach suggested recently is to use a his-ders. Cognitive impairment is an important feature in
tone deacetylase inhibitor to restore the transcrip-some of the early onset disorders such as ataxia telang-tional activity of the silenced frataxin gene
[23],

iectasia, ataxia with oculomotor apraxia, infantile-but clinical studies for these drugs have not been
onset spinocerebellar ataxia, Marinesco-Sjogren’s Syn-performed.

drome, and so on. Psychosis has been reported in some
The presence of psychosis usually warrants the
of these syndromes, in particular, late-onset Tay-Sachs
use of an antipsychotic drug. The likelihood of motor
Disease, cerebrotendinous xanthomatosis, and mito-symptoms in FRA would support the use of atypical
chondrial recessive ataxia, which are discussed else-in preference to classical antipsychotic drugs. Reports
where in this book.

335

Organic Syndromes of Schizophrenia – Section 3

References

imaging findings, and review of

Psychiatry Special Publication No

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4. Ashford, Kent: Headley

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