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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
Arch Neurol. 2001;58:201-205.
ABSTRACT
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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.
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.
Patients and Methods We reviewed 22 patients in 11 kindreds, identified through a systematic
survey of hereditary ataxias being conducted in Portugal.
Results Age at onset ranged from 1 to 15 years, with a 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.
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.
INTRODUCTION
OCULAR APRAXIA, defined as the limitation of ocular movements on command
dissociated from movements of pursuit, is a major clinical feature in 2 well-defined
hereditary ataxias, spinocerebellar ataxia type 2 and ataxia-telangiectasia
(A-T). In 1941, Louis-Barr1 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 x-rays, 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 mutation, 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, 9, 10, 11, 12)
with a neurologic picture similar 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.
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  -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.
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Table 1. Summary of Clinical Features in 22 Patients With AOA*
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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 Figure 1, 19 (86%) of the patients
experienced onset of the disease before school age. There was no sex difference
regarding the age at onset.
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Age at onset in the 22 Portuguese patients with ataxia and ocular
apraxia.
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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 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.
LABORATORY INVESTIGATION
Exclusion of A-T
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.
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 histogram 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).
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Table 2. Summary of Nerve and Muscle Biopsy Findings in Patients With
AOA*
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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 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.
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 large-diameter
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 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.
AUTHOR INFORMATION
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.
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.
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{at}hospitalfeira.min-saude.pt).
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