ORIGINAL CONTRIBUTION
Recessive Ataxia With Ocular Apraxia
Review of 22 Portuguese Patients
Clara Barbot, MD; Paula Coutinho, MD, PhD; Rui Chorão, MD; Carla Ferreira, MD; José Barros, MD;
Isabel Fineza, MD; Karin Dias, MD; José P. Monteiro, MD, PhD; António Guimarães, MD;
Pedro Mendonça, BSc; Maria do Céu Moreira, MSc; Jorge Sequeiros, MD, PhD
Background: The recessive ataxias are a heterogeneous group of neurodegenerative disorders characterized by cerebellar ataxia associated with a number of different neurologic, ophthalmologic, or general signs. They
are often difficult to classify in clinical terms, except for
Friedreich ataxia, ataxia-telangiectasia, and a relatively
small group of rare conditions for which the molecular
basis has already been defined.
mean of 4.7 years. The duration of symptoms at the time
of last examination varied from 5 to 58 years. All patients
presented with progressive cerebellar ataxia, the characteristic ocular apraxia, and a peripheral neuropathy. Associated neurologic signs included dystonia, scoliosis, and
pes cavus. Magnetic resonance imaging was performed in
16 patients, all of whom showed cerebellar atrophy.
Patients and Methods: We reviewed 22 patients in
11 kindreds, identified through a systematic survey of
hereditary ataxias being conducted in Portugal.
Conclusions: Ataxia with ocular apraxia may be more
frequent than postulated before, and may be identified
clinically using the following criteria: (1) autosomal recessive transmission; (2) early onset (for most patients
in early childhood); (3) combination of cerebellar ataxia,
ocular apraxia, and early areflexia, with later appearance of the full picture of peripheral neuropathy; (4) absence of mental retardation, telangiectasia, and immunodeficiency; and (5) the possibility of a long survival,
although with severe motor handicap.
Results: Age at onset ranged from 1 to 15 years, with a
Arch Neurol. 2001;58:201-205
Objectives: To study the clinical presentation and to
define diagnostic criteria in a group of Portuguese patients with ataxia and ocular apraxia, an autosomal recessive form without the essential clinical and laboratory features of ataxia-telangiectasia.
From the Department of
Pediatric Neurology, Hospital
Maria Pia (Dr Barbot),
Department of Neurology,
Hospital Santo António,
(Drs Ferreira, Barros, and
Monteiro), the Neuropathology
Unit, Hospital Santo António
(Dr Guimarães), and UnIGENe,
Instituto de Biologia Molecular e
Celular, University of Porto
(Drs Barbot, Coutinho, and
Sequeiros; Mr Mendonça; and
Ms Moreira), Porto; the
Departments of Neurology,
Hospital de São Sebastião, Santa
Maria da Feira (Dr Coutinho),
and Hospital de São Pedro, Vila
Real (Dr Chorão); and
Departments of Pediatric
Neurology, Hospital Pediátrico,
Coimbra (Dr Fineza), and
Hospital de D Estefânia, Lisboa
(Dr Dias), Portugal.
O
CULAR APRAXIA, defined as
the limitation of ocular
movements on command
dissociated from movements of pursuit, is a major clinical feature in 2 well-defined hereditaryataxias,spinocerebellarataxiatype2and
ataxia-telangiectasia (A-T). In 1941, LouisBarr1 described A-T as an autosomal recessive cerebellar ataxia beginning in early
childhood, associated with ocular apraxia,
choreoathetosis, oculocutaneous telangiectasia, immune dysfunction, chromosomal instability, and hypersensitivity to xrays, with a high incidence of respiratory
infections and neoplasias; it was associated with chromosomal instability and DNA
repair defects2 and mapped to chromosome 11.3 Spinocerebellar ataxia type 2 is
an adult-onset, autosomal dominant, cerebellar ataxia, first reported in India by Wadia and Swami,4 that has a large cluster in
the Cuban province of Holguin.5 The mu-
(REPRINTED) ARCH NEUROL / VOL 58, FEB 2001
201
tation, a CAG repeat expansion in the short
arm of chromosome 12, was identified in
1996.6
In 1988, Aicardi et al7 reviewed 14
patients (including 6 previously described
in Japan, Canada, and United Arab Emirates,8-12) with a neurologic picture similar
For editorial comment
see page 173
to that of A-T, but without any of its extraneurologic features. This new form of
recessive ataxia was considered rare, and
few reports were published thereafter.13,14 Through a systematic population
survey of inherited ataxias we are performing in Portugal,15 several new families with ataxia associated with ocular
apraxia (AOA) have been identified. We
decided therefore to study the clinical presentation of this peculiar disease and to define diagnostic criteria.
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PATIENTS AND METHODS
We studied 22 patients in 11 families of Portuguese
origin. Most patients have been ascertained during a
systematic, population-based survey of hereditary
ataxias and spastic paraplegias that is being conducted in Portugal.15 Initiated in 1993, the survey
has now covered 4 841 444 inhabitants, approximately half of the Portuguese population. Other
patients were referred by their assistant neurologists.
All were examined by one of us (C.B.) in a health
center or at home. Their parents and nonaffected
siblings were also examined. Whenever possible, the
proband from each family was hospitalized for further investigation, including cellular and humoral
immunological studies and a-fetoprotein (AFP) levels, electromyographic studies, and cranial magnetic
resonance imaging (MRI). Five patients underwent a
nerve biopsy.
RESULTS
Our series includes 8 male and 14 female patients (sex
ratio, 1:1.75). The age at last examination ranged from
9 to 60 years (mean age, 25.5 years), corresponding to a
disease duration of 5 to 58 years (mean duration, 20.8
years).
CLINICAL PRESENTATION
The main clinical features are summarized in Table 1.
Age at and Mode of Onset
The first manifestations, gait imbalance followed by
dysarthria, were noticed between 1 and 16 years of age
(mean age, 4.7 years). As illustrated in the Figure, 19
(86%) of the patients experienced onset of the disease
before school age. There was no sex difference regarding
the age at onset.
Cerebellar Ataxia
Ataxia was present in all 22 patients and was first defined by slowly progressive gait imbalance and dysarthria after initially normal motor development, followed by upper limb dysmetria, with mild intention
tremor.
Ocular Findings
Ocular apraxia is the most striking feature in this disorder, and was present in all 22 patients. It was never the
initial complaint, and was usually noticed a few years after the onset of gait ataxia. Patients appear not to fixate
normally on objects. When asked to look to one side, they
turn their head first, with eye contraversion, and then
their eyes follow in several slow saccades to the same side
with head thrusts. Ocular movements on command are
(REPRINTED) ARCH NEUROL / VOL 58, FEB 2001
202
usually slightly limited, with the eyes stopping before
reaching extreme positions. Eye and head movements
have an ataxic component. Besides being slow, they are
abrupt, dysmetric, and decomposed. These slow eye movements appear equally on lateral and vertical gaze, in the
same way. When the patients are standing, turning their
heads makes them lose their balance, and they tend to
move the whole body around. When the head is immobilized, the movement of the eyes is impossible. Blinking is exaggerated in most patients. Pursuit movements
remain normal during the first years after the appearance of ocular apraxia; then a progressive external ophthalmoplegia (beginning by upward gaze) is noticed (seen
in 14 [64%] of 22 patients). Oculocephalic reflexes are
spared until advanced stages of the disease.
Peripheral Neuropathy
All patients examined (with minimum disease duration
of 5 years) had generalized areflexia. A few years later,
distal muscular wasting and weakness appear, leading to
tetraplegia with extremely short, atrophic hands and feet.
Vibration and postural sense were impaired only in older
patients with very long disease duration. Pain and light
touch sensation were preserved.
Dystonia
There was a dystonic posturing of the upper extremities
in 13 patients (59%). In 3 of these patients, 2 from the
same family (family 9 in Table 1), dystonia associated
with masklike faces appeared early in the disease, and
was so relevant to the clinical presentation that those
patients underwent the diagnostic procedures for extrapyramidal disorders. In the other 10 patients, dystonia
was mild.
Other Signs
Pes cavus were present in 9 patients (41%) and scoliosis in 6 (27%). Three patients in the same kindred
(family 10 in Table 1) had optic atrophy beginning late
in life. No signs of extraneurologic involvement were
evident, except for obesity in 4 patients. Despite a long
evolution and extreme motor incapacity, there were no
signs of mental retardation or deterioration in our
patients.
Disability
Ataxia represented the main cause of disability in the
first stages of the disease. Later, peripheral neuropathy
dominated the clinical picture. Loss of the ability to
walk independently happened after 7 to 10 years of evolution, with most patients being wheelchair bound by
early adulthood.
Survival
Two patients died, one of a thalamic tumor at 11 years
of age, the other at 53 years of age after long-standing
disability and a disease duration of 52 years.
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Table 1. Summary of Clinical Features in 22 Patients With AOA*
Patient
Age at
Age at Last
Disease
Pes MRI/CT
EMG
Nerve
No. Family Consanguinity Sex Onset, y Examination, y Duration, y PEO Dystonia Neuropathy Cavus Findings Findings Biopsy
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1
1
1
2
3
4
4
4
5
5
5
5
6
6
7
8
9
9
10
10
10
11
+
+
+
−
+
−
−
−
+
+
+
+
−
−
−
−
−
−
+
+
+
+
F
F
F
M
F
F
F
M
F
F
F
M
F
M
F
M
M
F
F
M
M
F
5
5
15
16
6
2
2
2
4
4
3
5
10
5
5
1
3
2
1
1
1
5
10
60
55
25
21
21
9
20
13
11
9
10
16
18
14
18
21
23
50
52
59
26
5
55
40
9
15
19
7
18
9
7
6
5
6
13
9
17
18
21
49
51
58
21
−
+
+
+
−
+
−
+
−
−
−
−
+
+
+
+
+
+
+
+
+
−
−
−
−
−
−
+
+
+
−
+
+
+
+
+
+
+
+
+
−
−
−
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
−
−
−
+
−
−
+
+
−
−
−
−
−
+
+
+
+
−
−
+
+
−
CA
CA
ND
CA
CA
ND
CA
CA
CA/BSA
ND
CA
CA/BSA
CA/BSA
CA
CA
CA
CA
CA/BSA
ND
CA
ND
CA
N
PN
PN
PN
PN
ND
PN
PN
ND
ND
ND
N
PN
PN
PN
ND
PN
PN
ND
PN
ND
PN
ND
ND
ND
ND
ND
ND
ND
PN
ND
ND
ND
ND
PN
ND
ND
PN
PN
PN
ND
ND
ND
ND
Special
Features
...
...
...
...
Obesity
...
...
...
...
...
...
...
...
...
...
...
Obesity
Obesity
Optic atrophy
Optic atrophy
Optic atrophy
Obesity
*All patients had both ataxia and ocular apraxia. AOA indicates ataxia with ocular apraxia; PEO, progressive external opthalmoplegia; MRI, magnetic resonance
imaging; CT, computed tomographic scanning; EMG, electromyographic study; CA, cerebellar atrophy; N, normal; ND, not done; ellipses, no special features;
PN, peripheral neuropathy; BSA, brainstem atrophy; N, normal; PN, peripheral neuropathy; BSA, brainstem atrophy; plus sign, positive; and minus sign, negative.
LABORATORY INVESTIGATION
7
All
Male Patients
Female Patients
6
Exclusion of A-T
No. of Patients
5
Levels of AFP and immunoglobulins were normal in the
11 probands. In 4 patients studied, no cytogenetic abnormalities of chromosomes 7 and 14 were found.
4
3
2
Exclusion of Friedreich Ataxia
Nineteen patients from 10 families with AOA have undergone testing for GAA expansions at the gene for Friedreich ataxia. All of these patients had alleles of normal
size.
Neurophysiological Studies
Electromyographic studies were performed in 15 patients. An axonal neuropathy was found in 12; the other
2 patients with normal results underwent investigation
at a very early stage of the disease.
Nerve Biopsy
Nerve biopsies were performed in 5 patients
(Table 2). In 4 of these (patients 8, 13, 16, and 18),
the myelinated fiber density was reduced, due to the
absence of large-diameter fibers. The histograms
showed unimodal findings, with fiber diameters ranging
from 2 to 10 µm and a peak at 3- and 4-µm fibers. The
other patient (patient 17, the brother of patient 18)
underwent nerve biopsy earlier in the disease course.
The density of myelinated fibers was normal; the histo(REPRINTED) ARCH NEUROL / VOL 58, FEB 2001
203
1
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18
Age at Onset, y
Age at onset in the 22 Portuguese patients with ataxia and ocular apraxia.
gram still showed bimodal results, but with 1 abnormally short peak at 10-µm fibers. Degenerating myelinated fibers were present in patients 13, 17, and 18. No
“onion bulbs,” ie, regenerating clusters of fibers with
abnormally thin myelin sheaths, were observed. Electron microscopic study of all cases did not disclose evidence of storage diseases. Three of these patients also
underwent muscle biopsies. In patient 13 there was an
evident small-group atrophy, and in patients 8 and 18, a
severe large- and small-group neurogenic atrophy.
There was no evidence of reinnervation of muscle fibers
(ie, no type grouping).
Neuroimaging
Seventeen patients showed evidence of cerebellar atrophy on MRI (n = 16) or computed tomographic scan
(n=1). In addition, 4 patients (with 5, 6, 9, and 21 years
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Table 2. Summary of Nerve and Muscle Biopsy Findings in Patients With AOA*
Patient No.
Myelinated Fiber Density,
No./mm 2
Histogram
(Range of Fiber Diameters, µm)
Degenerating
Fibers
8
13
16
17
18
Reference values†
6610
7520
8030
10 760
6600
9450-11 960
Unimodal (2-7)
Unimodal (2-10)
Unimodal (2-9)
Bimodal (2-13)
Unimodal (2-10)
Bimodal (2-15)
No
Yes
No
Yes
Yes
NA
Neurogenic
Muscular Atrophy
Yes
Yes
...
...
Yes
NA
*AOA indicates ataxia with ocular apraxia; NA, not applicable; and ellipses, not examined.
†Includes 4 patients aged 3, 13, 14, and 16 years (control group for reference values).
of evolution) had atrophy of the brainstem. One of
the oldest patients (with 55 years of evolution of the disease) had a spontaneous hyperintensity of the dentate
nuclei on T2-weighted MRI.
FAMILY STUDIES
In each family, all patients appeared in the same sibship, except for one kindred with a pseudodominant pattern of inheritance explained by successive consanguineous matings (family 1), and another in which patients
appeared in 2 sibships (family 5). There was a history of
consanguinity in 5 kindreds. Three patients, with no evidence of parental consanguinity, represented isolated
cases.
The most relevant features of each family are summarized in Table 1. A homogeneous age at onset was verified in 9 families. As is often the case, the eldest affected
member of the sibship tended to have a reportedly later
onset, because of the family’s awareness of the disease.
All families also showed a complete homogeneity in the
neurologic expression of the disease.
GEOGRAPHIC DISTRIBUTION
IN PORTUGAL
Most patients with AOA came from the northern and central regions of mainland Portugal, but there was no evidence of geographic clustering of the disease, even when
considering their residence or the place of origin of the
oldest known members of the family.
COMMENT
Autosomal recessive AOA is a well-defined condition in
clinical terms. The main key to the diagnosis is the
presence of ocular apraxia. This feature nevertheless
may be overlooked. In early phases of the disease, the
examiner may not be familiar with it; in advanced cases,
the external ophthalmoplegia can mask the ocular
apraxia.
The differential diagnosis of AOA vs A-T, a multisystemic disorder, is based on the absence of telangiectasia, immunodysfunction, cytogenetic abnormalities of
chromosomes 7 and 14, and normal levels of AFP. This
exclusively neurologic involvement, without the complications of infection, cancer, or premature aging, allows AOA patients a much longer survival.
(REPRINTED) ARCH NEUROL / VOL 58, FEB 2001
204
Another important feature in our series of patients
is the presence of an axonal peripheral neuropathy, with
very early areflexia. This neuropathy dominates the clinical picture in the advanced phases of the disease and is
the major cause of disability in these patients, who remain tetraplegic for several years, confined to a wheelchair, and with marked distal atrophies. Pathologically,
this neuropathy is characterized by the absence of largediameter fibers and preservation of the small-diameter
fibers, without any evidence of regeneration. The motor
neuropathy is also demonstrated by the neurogenic atrophy present in muscle biopsy findings.
Dystonia was present in 13 patients, although it is
sometimes difficult in ataxic patients to be certain that
the position (particularly of the hands) we are calling dystonia is not just extreme ataxia. One family initially underwent investigation for a progressive dystonia.
Cerebellar atrophy was a consistant finding in our
patients; it was sometimes combined with brainstem atrophy. No correlation was found between the brainstem involvement and the disease duration. These MRI
findings are one of the main features in the differential
diagnosis of AOA vs Friedreich ataxia, along with the
earlier onset in AOA.
The clinical picture of AOA is strikingly repetitive.
Through our survey in Portugal, another group of recessive ataxias with peripheral neuropathy but without ocular apraxia has been detected. We wonder whether, when
a molecular diagnosis is available, the spectrum of the
disease will cover other clinical variants. Comparing the
present series with the previous description by Aicardi
et al,7 we found a great constancy and prominence of the
peripheral neuropathy and existence of cerebellar atrophy in all patients. Our data also gave an overview of the
natural course of AOA that is in disagreement with the
findings of Gascon et al,13 who found a nonprogressive
course after initial gait deterioration. Autosomal recessive ataxia with ocular apraxia is a progressive condition allowing, in any case, very long survivals until late
adulthood.
One hundred seven patients in 80 families with
recessive ataxia have been identified so far through
our survey in Portugal. Friedreich ataxia, as expected,
is the most frequent diagnosis (38% of the patients),
followed immediately by AOA (21% of the patients).
Based on our own experience and the findings of previous reports, we propose the following clinical criteria
for AOA: (1) autosomal recessive transmission; (2) early
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onset (for most patients in early childhood); (3) combination of cerebellar ataxia, ocular apraxia, and early areflexia, with the later appearance of a full picture of peripheral neuropathy; (4) absence of mental retardation,
telangiectasia, and immunodeficiency; and (5) the possibility of a long survival, although with severe motor
handicap.
Accepted for publication May 24, 2000.
This study was supported by grant 207 from the
Comissão de Fomento da Investigação em Cuidados de Saúde
(Portuguese Ministry of Health), Lisbon, and grants from
Fundação para a Ciência e Tecnologia (Portuguese Ministry of Science and Technology) and the Portuguese Health
Administration (projects STRDA/C/SAU/277/92 and PECS/
C/SAU/219/95), Lisbon.
We thank all patients and their families for participating in this study, and their physicians for referring them
to our national survey of hereditary ataxias and spastic
paraplegias in Portugal.
Corresponding author and reprints: Paula Coutinho,
MD, PhD, Division of Neurology, Department of Medicine,
Hospital de São Sebastião, 4520-211 Santa Maria da Feira,
Portugal (e-mail: pcoutinho@hospitalfeira.min-saude.pt).
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