Download Joubert syndrome: long-term follow-up

Joubert syndrome:
long-term follow-up
Peter R Hodgkins* FRCS FRCOphth;
Christopher M Harris PhD;
Fatima S Shawkat PhD;
Dorothy A Thompson PhD, Department of Ophthalmology;
Kling Chong MD FRCR, Department of Neuroradiology;
Christine Timms DBOT;
Isabelle Russell-Eggitt FRCS FRCOphth;
David S Taylor FRCS FRCOphth FRCP;
†Anthony Kriss PhD, Department of Ophthalmology, Great
Ormond Street Hospital for Children, London, UK.
*Correspondence to first author at Southampton Eye Unit,
Southampton General Hospital, Tremona Road,
Southampton SO16 6YD, UK.
E-mail: [email protected]
Twenty-nine patients (16 males, 13 females) with Joubert
syndrome were identified from ophthalmology, neurology, and
genetic databases covering a 15-year period at Great Ormond
Street Hospital, London. Criteria for diagnosis included absent
or markedly hypoplastic cerebellar vermis, abnormal eye
movements, and developmental delay. Five patients had died.
Scans and notes were available for 22 patients, and 18 cases
were clinically reviewed. The median age was 10 years 10
months (range 3mo to 19y) and the median follow-up was 8
years 5 months (range 3mo to 19y, with one new patient seen
at 3mo of age). Cerebellar vermis hypoplasia/aplasia with
‘molar tooth sign’ in the axial plane was present in 22 of 22
patients, coloboma in 6 of 22, and polydactyly in 6 of 22. In
the 18 clinically reviewed, apnoea occurred in 13 patients.
Five had renal problems with cysts and 4 of 5 had abnormal
electroretinograms (ERGs). Visual electrophysiology was
abnormal in 14 of 18 patients, and in 6 there was evidence of
deterioration in the ERG. Blood investigations of organic
acids, phytanic acid, very-long-chain fatty acid, and
transferrin were normal in 12 patients tested. Developmental
assessment showed that 6 of 15 patients aged more than 5
years were at mainstream school, and 12 of 18 had started
walking between 22 months and 10 years. Speech difficulties
and behavioural problems were prominent.
See end of paper for list of abbreviations.
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Developmental Medicine & Child Neurology 2004, 46: 694–699
Joubert syndrome is an autosomal recessive disorder named
after Marie Joubert (Joubert et al. 1969), who, with her coworkers, characterized four patients with episodic tachypnoea and
apnoea, abnormal eye movements, developmental delay, ataxia,
and absence of the cerebellar vermis. Dekaban (1969) described
two siblings with the same clinical findings who also had a retinal
dystrophy: this has been described as a congenital retinal dystrophy (Aicardi et al. 1983). Boltshauser and Isler (1977) proposed that the condition, with or without retinal dystrophy,
should be referred to as Joubert syndrome, but others have
suggested the term ‘Debekan syndrome’ for the subgroup with
retinal dystrophy (Saraiva and Baraitser 1992). Boltshauser et
al. (1995) reviewed a series of 12 patients and identified a subgroup of patients within Joubert syndrome with both renal
involvement and a retinal dystrophy. Others have subsequently
reviewed the diagnostic criteria for Joubert syndrome (Maria et
al. 1999, Merritt 2003). The classical neuroimaging finding is of
cerebellar vermis abnormalities with the following features:
minimal connection between both cerebellar hemispheres;
umbrella-shaped fourth ventricle; and stretched superior cerebellar peduncles and deep interpeduncular fossa leading
to the ‘molar tooth sign’ of the mesencephalon, which is a
description of the appearance seen on cross-sectional images
taken in the axial plane (Maria et al. 1999, McGraw 2003).
Since its first description, a range of other clinical findings
have been described in association with Joubert syndrome
including occipital meningoencephalocele (Joubert et al.
1969, Houdou et al. 1986), dysmorphic facies (Wilson and
Waber 1992), duodenal atresia (Lambert et al. 1989), facial
palsy (Joubert et al. 1969, Boltshauser et al. 1981), cystic kidneys (King et al. 1984), congenital hepatic fibrosis (Lewis et al.
1994), polydactyly (Egger et al. 1982, Kher et al. 1994), tongue
tumours (Egger et al. 1982), and ocular fibrosis (Appleton et
al. 1989, Jacobsen et al. 1992). Ocular findings have included
chorioretinal coloboma (Lindhout et al. 1980, Laverda et al.
1984, Beemer and Gooskens 1985, Kher et al. 1994), ptosis
(Harmant-Van Rijckevorsel et al. 1983, Houdou et al. 1986),
saccade initiation failure (ocular motor apraxia; Moore and
Taylor 1984, Lambert et al. 1989, Harris et al. 1996), nystagmus
(Joubert et al. 1969, Lambert et al. 1989), and strabismus
(Moore and Taylor 1984). Biochemical abnormalities have also
been described: histidinaemia (Appleton et al. 1989) and
Gauchers type 1 (van Royen-Kerkhof et al. 1998).
Little is known about the long-term outcome of Joubert syndrome. Some authors suggest that nearly all living children
with this disorder have severe disabilities (Boltshauser et al.
1977, Curatolo et al. 1980, Aicardi et al. 1983, Gitten et al.
1998) and that both cognitive and motor functions will deteriorate with time (Cantani et al. 1990). Others have indicated a
much better outcome (Zeigler et al. 1990). In the present study
we recalled and reviewed all patients diagnosed as having
Joubert syndrome over the past 15 years at the Great Ormond
Street Hospital for Children, London, to establish the clinical
outcome, assess any evidence of progression, and look for evidence of biochemical abnormalities.
Methods
The study was performed at Great Ormond Street Hospital
for Children. Ethical approval was obtained from the hospital’s ethics committee, and informed consent was obtained
from the parents of each patient. Patients with a diagnosis of
Joubert syndrome were located from the ophthalmology,
neurology, and genetic departments’ databases. Diagnosis
depended upon the presence of abnormal neonatal breathing, abnormal eye movements, developmental delay, and an
abnormal cerebellar vermis. The case notes, blood results,
renal tract investigations, and computerized tomography (CT)
or magnetic resonance imaging (MRI) scans were reviewed
and arrangements were made to recall the patients. Those
examinations that had previously been inadequate or overlooked were repeated at recall.
Each recalled patient underwent a renal ultrasound, a neuroophthalmological review, formal eye movement recordings,
electroretinograms (ERGs), visual evoked potentials (VEPs),
and an eye examination that included visual acuity assessment, slit lamp microscopy of the anterior segment, cycloplegic
refraction, and fundoscopy. Biochemical studies were also performed with consent. These included liver function tests, urea
and electrolytes, very-long-chain fatty acids, pipecolic acid, and
histidine.
VISUAL ELECTROPHYSIOLOGY
Mixed rod–cone ERGs were recorded from skin electrodes
positioned close to the lower eyelid margin or from DTL
fibre electrodes (Dawson et al. 1979) depending on patient
cooperation. A photic stimulator (GrassPS22; 3/sec, setting 4,
peak intensity 4.75×106 lumens) provided flash stimulation
under scotopic conditions (see Kriss and Thompson 1997
for details of the protocol). Responses were averaged with a
Sensor ER94 (Medelec, Oxford, UK). Flash VEPs were recorded at the same time as ERGs. Pattern reversal stimulation was
attempted for each patient. A range of black and white
checkerboard stimuli (subtending 400′, 200′, 100′, 50′ and
25′ check size) were counterphased 3/sec on a monitor subtending 28˚×21˚. The VEPs were recorded from electrodes
positioned at the inion and 3.5cm above it (Oz, International
10–20 system; Jasper 1958). An electrode at Fz (International
10–20 system) served as the common reference.
EYE MOVEMENT RECORDING
Horizontal eye movements were recorded with direct-current electro-oculography. Silver–silver chloride electrodes were
attached with tape at the outer canthus of each eye, with a
reference electrode at the mid-forehead. Video monitoring
of the patient was performed throughout the recording session. Infrared monitoring was used when testing the vestibulo-ocular reflex in absolute darkness.
Optokinetic nystagmus was elicited by rotating a brightly
coloured and patterned full-field curtain around the patient.
Leftward and rightward optokinetic nystagmus at speeds of
25 and 50˚/sec were recorded. Rotating the patient on the
Barany chair (motorized rotating chair) while in complete
darkness tested vestibulo-ocular reflex. The chair was accelerated at 18˚/sec to a speed of 80˚/sec and this speed was
maintained for 40 seconds before decelerating at 18˚/sec to
rest. After a further 40 seconds the chair was rotated in the
opposite direction. For a full description of protocol see Jacobs
et al. (1992) and Harris et al. (1992).
Results
Twenty-nine patients (16 males, 13 females) were identified as
having Joubert syndrome as their final diagnosis. This included
four pairs of siblings. Eleven patients were unavailable for
review: five (18%) patients had died (two from respiratory
failure [age under 1 year], two from renal failure, and one from
aspiration pneumonia secondary to a cleft palate under 1 year);
one was in renal failure having dialysis after a failed transplant;
two patients (siblings) had migrated; two other siblings had
been adopted with no trace; and a further one unrelated patient
declined re-attending the department. Details were used when
available and relevant to the study.
Therefore, eighteen patients (11 males, 7 females) were
reviewed in this study. Median age was 10 years 10 months
(range 3mo to 21y) with a median of 8 years 5 months’ (range
3mo to 19y) follow-up (one patient was seen as a new case at 3
months old). Four pregnancies were reported as abnormal: in
two of them the pregnancy had been complicated with polyhydramnios (one with duodenal atresia, one with rhesus disease), one was born with meconium staining of the liquor, and
one was induced because there was a leak of amniotic fluid.
NEURORADIOLOGY
MRI and/or CT were reviewed in 22 patients. Cerebellar vermis aplasia/hypoplasia was present in 22 of 22 patients. The
vermis was aplastic in eight and hypoplastic in 14 patients,
affecting mainly the postero-inferior part. In all these cases
the midbrain and superior cerebellar peduncles displayed
the ‘molar tooth appearance’.
Associated features were noted on the MRI/CT scans of
five patients. These were brainstem hypoplasia in two, occipital meningocele in one, corpus callosum dysgenesis in one,
moderate dilation of the ventricular system in one, and nonspecific high signal lesions in the white matter in a patient
who also had seizures.
CLINICAL AND BIOCHEMICAL ASSOCIATIONS
Associated systemic features in 22 patients were as follows:
bilateral tight Achilles tendons (n=2); pyloric stenosis (n=1);
thoracic scoliosis (n=2); general joint laxity (n=3); haemangioma (n=3); duodenal atresia (n=1); keratoconus (n=1);
partial third nerve palsy (n=1).
One sibling had a tracheo-oesophageal fistula and another
sibling had anophthalmos.
EEG was recorded in 10 patients and was abnormal in five:
two of five had seizures; two of five had sharp discharges over
focal areas but no recognizable epilepsy (one with rightsided occipital seizures and one with sharp discharges over
right frontal lobe); the fifth had infrequent paroxysmal features of a multifocal distribution consistent with the MRI of
multifocal white matter intensities.
Apnoeic episodes occurred in 13 of 18 patients, and in 10
of them they were a transient phenomenon lasting up to 3
months. One patient spent several weeks in the paediatric
intensive care unit because of severe tachypnoeic episodes;
another required oxygen at home; and a third patient had
apnoeic episodes until 18 months of age.
Chorioretinal coloboma were seen in six of 22 patients.
Postaxial polydactyly was present in six of 22: both were present in only three patients.
Five patients had renal cysts, and four of these also had an
abnormal ERG. The fifth patient with ultrasound evidence of
multiple renal cysts had normal ERGs but was only 2 years
old. The other 13 patients were normal in this respect.
Organic acids, phytanic acids, very-long-chain fatty acids and
amino acids were normal in 12 patients tested. Plasma transferrin isoelectric processing had been performed in 10 patients; it
Joubert Syndrome Peter R Hodgkins et al. 695
was performed as part of tests to exclude other diagnoses,
and this was also normal. Routine karyotype was normal in
10 patients tested. Muscle biopsy was performed on two
patients and was normal.
DEVELOPMENTAL FINDINGS
Discussion with the parents and note letter review revealed
that general hypotonia was an early observation in all 18
patients. All patients also demonstrated some degree of motor
and developmental delay, although this varied from mild to
very severe. Twelve of 18 patients had walked unaided with a
broad-based gait between 22 months and 10 years (one with
orthosis, reason unclear). The corresponding times for sitting unaided and standing were delayed.
No formal speech assessment or IQ assessment was performed during the study. However, all children were attending
or had attended speech therapy. Of those 15 children over 5
years old, 11 had developed intelligible speech and six
were attending mainstream school. Even in those six children,
speech remained a problem with difficulty in pronouncing
words such that, in many cases, the parents could understand
but newcomers had difficulty. Five had mild disability although
they had achieved toilet training and self-feeding. Four had
severe disability, with failure to develop even these basic skills.
In eight of 15 cases, parents volunteered the occurrence of
severe temper tantrums and confirmed a large differential
between comprehension and verbal ability.
EYE MOVEMENT FINDINGS
Saccade initiation failure (ocular motor apraxia) was evident
in 14 of 18 patients; there was a variable failure of quick phases during induced optokinetic nystagmus or vestibular nystagmus, causing the eyes to deviate to the mechanical limit of
gaze (i.e. locking up). In 13 patients the locking up was intermittent, but in one it was total with no saccades observed. Of
these, eight exhibited head thrusting as a compensatory behaviour to shift the direction of gaze, and a further three patients
showed synkinetic blinks where previously head thrusting
had been recorded.
Five patients were associated with torsional nystagmus, three
with horizontal pendular nystagmus, and two with upbeat
nystagmus. One patient exhibited skew deviation and three
had alternating gaze deviations, which were reminiscent of
ping-pong gaze in one but were noticably aperiodic in the
other two.
There was one patient with a convergent squint, five with
divergent squints, and five with alternating vertical squints.
Table I: Visual acuity (Snellen) and associated retinal
involvement (n=18)
Visual acuity
No retinal involvement
Retinal involvement
6/6 to 6/9
2
1
6/12 to 6/18
2
6
6/24 to 6/60
0
3
<6/60
0
4
Total, n
4
14
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Developmental Medicine & Child Neurology 2004, 46: 694–699
VISUAL ELECTROPHYSIOLOGY
A normal flash with a well-preserved pattern VEP to small
and medium-sized checks (subtending 25′ to 100′), suggesting good acuity levels, with a normal ERG, was found in four
of 18 patients. However, in one of these patients the ERG
was reduced in amplitude although still within the normal
range. These findings were stable over the follow-up period
(mean 6 years).
Retinal responses were markedly abnormal in the remaining
14 of 18 patients, with the flash ERGs being significantly attenuated and degraded. In 10 of these 14 patients, flash and pattern reversal VEPs could be elicited, but in the remaining four
only attenuated flash VEPs were evident, indicating that vision
was at a rudimentary level only. In six patients there was evidence of deterioration according to the ERG recordings over
the follow-up period.
OCULAR EXAMINATION
Anterior segment examinations were normal in all the 18
patients clinically reviewed. Fundal examination in those
patients with an abnormal ERG revealed retinal pigment
epithelium mottling in all 14 patients. In four of these patients
with abnormal ERG and only a very attenuated flash VEPs,
there was marked mottling of the retinal pigment epithelium,
especially at the macular area. In the remaining four of 18
patients with normal visual electrophysiology (VEPs and ERGs)
the fundal examinations were normal.
Table I summarizes the visual acuities in the 18 patients, and
their relationship with retinal involvement. It can be seen that
poor levels of acuity (less than 6/24) are associated with retinal
involvement. Interestingly, two patients with moderate levels of
vision (6/12 to 6/18) had no retinal involvement and the reduced
vision seems most likely to have been due to nystagmus.
Discussion
The diagnosis of Joubert syndrome as opposed to other similar
clinical conditions is difficult because of the current absence
of a specific test or genetic marker (Blair et al. 2002). Several
syndromes that have been considered distinct from Joubert
syndrome have occasionally been grouped clinically with it,
including cerebello-oculo-renal syndromes (Satran et al. 1999).
In the present study every effort was made to include only those
patients that the departments of neurology, ophthalmology,
and genetics all agreed have Joubert syndrome. The criteria
used were the presence of developmental delay, abnormal ocular movements, and the presence of marked cerebellar vermis
abnormalities leading to the presence of the ‘molar tooth sign’
(Maria et al. 1999, McGraw 2003).
In four inherited syndromes, Dandy–Walker malformation,
cerebellar vermis hypoplasia–oligophrenia–ataxia–coloboma
and hepatic fibrosis syndrome (COACH), carbohydrate-deficient glycoprotein syndrome (CDG), and Joubert syndrome,
the finding of cerebellar vermis hypoplasia or aplasia with
multiple other ocular and systemic findings usually provides
the basis for differential diagnosis (see Table II). Others have
looked at the similarity between CHARGE (coloboma of the
eye, heart defect, atresia of the choana, retarded growth and
development, genital hypoplasia, and ear anomalies or deafness) and Joubert syndrome (Menenzes and Coker 1990).
Di Rocco (1993) suggests that Joubert syndrome with retinal dystrophy and renal cysts might represent CDG, and CDG
must be considered in any patient with cerebellar dysplasia
and renal or liver cysts. It can be excluded by performing isoelectric focusing of plasma transferrin, which is carbohydrate
deficient in affected patients. Orofacial digital syndrome also
needs to be considered as potentially overlapping with Joubert
syndrome; Smith and Gardner-Medwin (1993) describe a
brother and a sister with learning disability,* malformations of
the cerebellar, characteristic metronome eye movements, lingual hamartomas, and postaxial polydactyly.
Cerebellar vermian dysgenesis is a cardinal feature in
Joubert syndrome; all of the patients in our study exhibited
this sign, with the presence of the ‘molar tooth sign’ in the
axial plane. The association of Joubert syndrome with more
profound hypoplasia postero-inferiorly was confirmed. A
review of all the scans for other problems did not lead to any
constant or common other associations. The hypoplastic
cerebellar vermis could explain only motor problems and
not any associated learning disability. Even a review of the
cerebral cortex on those MRIs performed recently revealed
no abnormality.
DEVELOPMENTAL FINDINGS
Many of the reports so far have tended to indicate a poor
developmental prognosis for these patients. It was thought
that all living children with the disorder have severe disabilities (Boltshauser et al. 1977, Curatolo et al. 1980, Aicardi et al.
1983, Calleja-Perez et al. 1998). Severe learning disabilities are
generally accepted as an integral part of Joubert syndrome
(Gitten et al. 1998). However, there are reports on older
patients with Joubert syndrome that have drawn attention to
the possibly better than expected outcome. Casaer et al.
(1985) described a patient who had possibly isolated agenesis
of the vermis but did have features of Joubert syndrome (transient early breathing abnormalities, irregular jerky eye movements). Zeigler et al. (1990) reported on one child aged 8 years
with Joubert syndrome: although severe learning disability
was evident until about the age of 5 years, unexpected and
exceptional capabilities were evident at a later follow-up.
In this study we followed up a group of these children and
conclude that severe learning disability is not an absolute
feature of the syndrome. Six of 15 children in our study were
older than 5 years and were attending mainstream school
with varying amounts of help. The eye movement abnormalities together with severe motor disorder can give an early false
impression of the severity of intellectual disability. Gitten et al.
(1998) have reported that the degree of developmental delay
and the severity of central nervous system malformations seem
to be independent. The severe motor difficulties that are experienced in this syndrome, together with the eye movement
problems and speech difficulties, create a barrier to effective
communication so that early intellectual and emotional
development are hard to assess. Failure to recognize this can
lead to affected children being labelled as having a disability.
Steinlin et al. (1997) reported 19 children with Joubert syndrome with variable motor and cognitive development. Our
study supports this observation. In all of our patients there
was a differential delay, with motor development being most
affected and comprehension abilities almost uniformly being
reported as ahead of other abilities.
In eight patients with good comprehension skills yet poor
vocalization, the parents reported prominent temper tantrums.
It has been suggested that this might be due to difficulty in
vocalization. Twelve patients were undergoing speech therapy.
There is a strong relationship between articulatory deficits
and saccade initiation failure (Harris et al. 1996, Jan et al.
1998), and this might be attributable to vermis malformation
(see Harris et al. 1998).
OCULAR FINDINGS
Joubert syndrome is often associated with retinal problems,
*US usage: mental retardation.
Table II: Summary of diagnostic clinical features for Joubert syndrome and other similar clinical conditions
Feature
Joubert syndrome
Dandy–Walker
malformation
CHARGE
CDG
COACH
Leber’s
amaurosis
ERGs can be
attenuated
Apnoea, breathing
Yes; episodic
tachypnoea/apnoea
MRI
Vermis hypoplasia,
brainstem malformation
(‘molar tooth sign’)
Normal ERGs
Normal ERG
Attenuated ERG
Normal ERG
No
No
No
No
Attenuated/
absent ERG
No
Normal
Olivopontocerebellar
atrophy
Vermis
hypoplasia
Normal
Yes
Yes
SIF, skew deviations,
nystagmus
Vermis hypoplasia,
cystic dilatation
4th ventricle,
hydrocephalus
Yes
No
SIF, pendular
nystagmus
No
No
Nystagmus,
roving EM
Sometimes
Yes
–
Yes
No
Cerebellar EM:
nystagmus, saccadic
pursuit
No
No
Cardiomyopathy,
polyneuropathy
Yes
Yes
SIF, nystagmus
Sometimes
Yes
–
No
Yes
Nystagmus
if very
poor vision
No
No
–
No
Yes
Hepatic
No
No
–
Retinopathy ERG
Ataxia
Coloboma
Eye movements
Polydactyly
Renal involvement
Other
CHARGE, coloboma of the eye, heart defect, atresia of the choana, retarded growth and development, genital hypoplasia, and ear anomalies or
deafness; CDG, carbohydrate-deficient glycoprotein syndrome; COACH, cerebellar vermis hypoplasia–oligophrenia–ataxia–coloboma and
hepatic fibrosis syndrome; ERG, electroretinogram; SIF, saccadic initiation failure; EM, eye movements.
Joubert Syndrome Peter R Hodgkins et al. 697
which were originally described by Dekaban (1969) and were
not reported by Joubert et al. (1969) in their cases, leading to a
suggestion that two different names be used depending on
the presence of a retinal dystrophy. Although our protocol is
to record VEP and ERG simultaneously, previous studies of
Joubert syndrome have recorded ERGs alone and Joubert
syndrome has been associated with very attenuated or undetectable rod-mediated ERGs previously classified as a variant
of Leber’s amaurosis (Tomita et al. 1979, King et al. 1984,
Moore and Taylor 1984).
Our findings support the reports in the literature that retinal abnormalities occur in a sub-group of patients carrying the
diagnosis of Joubert syndrome (Boltshauser and Isler 1977,
Saraiva and Baraitser 1992, Boltshauser et al. 1995). Visual
electrophysiology had been performed in 18 patients and was
found to be abnormal in 14 of them. Among the four normal
recordings were those from the youngest patients in our study,
and one of them had evidence of deterioration although still in
the normal range. We found evidence of progressive retinal
damage in six other patients with longer follow-up. Failure to
detect any deterioration in other patients’ ERGs might have
several explanations. The original recording showed that function might have been so severely affected as to be almost not
recordable so that small changes made very little difference, or
there was inadequate follow-up on some patients. In four of
14 patients with abnormal ERGs, the ERG and VEP could not
be detected from background activity and the patients effectively had total visual impairment. Examination of the fundi of
these patients revealed mottling of the retinal pigment epithelium, especially at the macula area.
Saraiva and Baraitser (1992) concluded that retinal dystrophy runs in families and is never absent when renal cysts
are present. The renal cysts are multiple, small, and cortical,
and affected kidneys also have interstitial chronic inflammation and fibrosis. We found renal abnormalities in five patients,
all of whom had undergone visual electrophysiology; in four
of them this was abnormal. However, there was one patient
with a prominent cyst on renal ultrasound who had normal
electrophysiology. This exceptional patient was 2 years old
and only a single recording had been made, so it is possible
that a retinal abnormality might develop later. Unfortunately
review was not possible.
EYE MOVEMENTS
A range of eye movement abnormalities were present, the
most common being saccade initiation failure, which was
seen in 13 of 18 patients reviewed.
It is not possible to relate the eye movement abnormalities to precise anatomical sites owing to the widespread malformations in Joubert syndrome. A recent post-mortem study
of Joubert syndrome (Yachnis and Rorke 1999) revealed not
only vermis aplasia but also malformations of the dentate
nuclei and atrophy of the cerebellar cortex. There were multiple medullary malformations including hypoplastic inferior
olives, thinning of the reticular formation neurons, displaced
tegmental nuclei (including vestibular nuclei), and a malformed cervicomedullar area involving the posterior median
sulcus, fasciculi gracilis and cuneatus, and solitary nucleus.
Saccade initiation failure has been associated with a wide
range of congenital and acquired conditions (see Cassidy et
al. 2000). However, there is a strong association of saccade
initiation failure with vermian malformations (Eda et al.
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Developmental Medicine & Child Neurology 2004, 46: 694–699
1984, Shawkat et al. 1995, Harris et al. 1998, Jan et al. 1998),
or acquired vermian lesions including tumours and neurodegenerative condition (Cassidy et al. 2000). In the Cassidy
study all had cerebellar vermis hypoplasia (eight had absent
vermis and 14 had hypoplastic vermis predominantly affecting the posterior-inferior part). Although vermis hypoplasia
seems the most likely cause of saccade initiation failure in
Joubert syndrome, the mechanism is unclear because primate vermis seems to be more involved with saccade accuracy than timing (discussed by Harris et al. 1998).
Nystagmus was seen in 10 of 18 patients. The nystagmus
was torsional in five of them and could not be measured by
our equipment. In four it was horizontal pendular and in one
it was upbeat. These varieties of nystagmus were not typical
of congenital sensory nystagmus even in those with an associated retinal dystrophy, and we attribute the nystagmus to a
neurological cause (Casteels et al. 1992) probably resulting
from brainstem malformation.
A peculiar observation in three children was periodic horizontal alternating gaze shifts, in which the eyes would swing
conjugately between extreme horizontal gaze position over
about 5 to 15 seconds. We have not seen this phenomenon associated with any other condition. It bears some resemblance to
periodic alternating esotropia (but without the esotropia)
described by Hamed and Silbiger (1992) in a patient with
hypoplasia of the vermis and brainstem. One possibility is that
the deviations reflect periodic alternating nystagmus without
quick phases (owing to saccade initiation failure; Harris 1997).
Conclusion
Retinal dystrophy is strongly associated with renal abnormalities. The retinal dystrophy in Joubert syndrome might be
progressive. Not all children affected have severe disabilities.
saccade initiation failure is not invariable.
DOI: 10.1017/S0012162204001161
Accepted for publication 5th March 2004.
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Tony Kriss died while this project was under way. His contributions
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List of abbreviations
CDG
ERG
VEP
Carbohydrate-deficient glycoprotein syndrome
Electroretinogram
Visual evoked potential
Joubert Syndrome Peter R Hodgkins et al. 699