1119

SCIENTIFIC REPORT

Batten disease: features to facilitate early diagnosis

J Collins, G E Holder, H Herbert, G G W Adams
...............................................................................................................................

Br J Ophthalmol 2006;90:1119–1124. doi: 10.1136/bjo.2006.091637

encoded for by CLN3, CLN5, CLN6, and CLN8.5 The majority

Aims: To ascertain the clinical and electrophysiological of cases of juvenile onset NCL are caused by mutations in
features in patients with juvenile neuronal ceroid lipofusci- CLN3 which maps to chromosome 16p21.6 To date 31
nosis (jNCL/Batten disease) and to identify those features that mutations in this gene have been reported, the commonest
facilitate early diagnosis. of which is a 1.02 kb deletion that is present on approxi-
Methods: Nine patients with jNCL were identified retro- mately 85% of disease chromosomes.7 Juvenile phenotypes
spectively and their case notes reviewed. All had undergone have also been observed following mutations in the CLN1 and
an extensive clinical examination, including electrophysiol- CLN2 genes.4 The primary biochemical defect in these
ogy. Blood and molecular genetic testing confirmed the disorders is yet to be ascertained and to date there is no
diagnosis. available treatment.
Results: Age at onset ranged from 4–8 years. At presenta- It is juvenile NCL (jNCL) that is of particular interest to the
tion, two of nine patients had normal fundi; only two of nine ophthalmologist as these children usually present with
patients had a bull’s eye maculopathy. The electroretinogram rapidly progressive visual failure between the ages of 4–
(ERG) findings in this series included undetectable rod 10 years, generally leading to legal blindness within 3 years.1
specific ERGs, an electronegative maximal response, The incidence of jNCL is estimated at up to one in 25 000
reduced and delayed cone flicker ERGs, reduction in the with an increased prevalence in north European populations.6
It is an important cause of childhood blindness in the United
b:a ratio in the photopic single flash ERG, and an
Kingdom as up to 25% of the children registered as blind each
undetectable pattern ERG. Vacuolated lymphocytes on
year presenting with retinal or macular disease may have
peripheral blood film testing were present in eight of nine jNCL.1
patients. Five of eight patients were homozygous for the Early diagnosis of jNCL by the ophthalmologist has several
1.02 kb deletion on the CLN3 gene on molecular genetic implications. In particular, it allows families to receive the
testing; two of eight patients were heterozygous for that appropriate counselling and also enables appropriate provi-
deletion. sion of educational and family support. The diagnosis is
Conclusion: jNCL should be considered in children of based on clinicopathological findings and can be confirmed
10 years and under presenting with visual loss and fundal by molecular genetic testing. Retinal signs include bull’s eye
changes ranging from normal through to pigmentary/ maculopathy, peripheral pigmentary or atrophic changes,
atrophic changes or a bull’s eye maculopathy. disc atrophy, and attenuation of retinal arterioles.2 However,
Electrophysiology may suggest jNCL. Although currently fundus examination at presentation may be normal causing
untreatable, early diagnosis is important to institute appro- great diagnostic difficulty. Features including behavioural
priate counselling and support. changes, cognitive impairment, motor disturbance, and
seizures follow the ophthalmic signs. The disease follows an
inexorable path to death in the second or third decade.1
Analysis of the peripheral blood film demonstrates vacuo-
lated lymphocytes with the characteristic fingerprint profile

T
he neuronal ceroid lipofuscinoses (NCL) are the com-
monest neurodegenerative disorders occurring in chil- pattern on ultrastructural appearance. The diagnosis is
dren and have an autosomal recessive pattern of confirmed by molecular analysis of the CLN3 gene, with the
inheritance.1 Batten in 1903 described two siblings with majority of disease alleles having the common 1.02 kb
progressive macular dystrophy and cerebral degeneration2 deletion. Electrophysiological testing may facilitate the early
and his name subsequently became associated with the diagnosis of jNCL and electroretinograms (ERGs) typically
juvenile form. Zemen and Dyken introduced the term NCL in demonstrate an electronegative waveform under both sco-
1969 and suggested that the autofluorescent material, which topic and photopic conditions.
accumulated within neurons and other cell types in these A series of patients with jNCL is reported and their clinical,
disorders, had histochemical properties similar to the electrodiagnostic, blood, and molecular genetic findings
lipopigments ceroid and lipofuscin.2 3 It has recently been ascertained to identify features for early investigation and
demonstrated that this material is two thirds protein.3 diagnosis of this condition. We also highlight the need for
support measures to be available once the diagnosis has been
Clinical features, including age of onset and the presence/
made. Some data on three of these patients have previously
ultrastructural appearance of this lysosomal storage material,
appeared.8 9
have traditionally classified NCLs as infantile, late infantile,
juvenile, and adult. The term Batten disease should refer only
to the juvenile onset form of NCL, but this eponym has been MATERIALS AND METHODS
applied to all NCLs.1 Current genetic classification of NCLs The case notes of 11 patients with NCL were reviewed.
distinguishes eight different disorders, which often encom- Patients were identified from records within the family
pass clinical heterogeneity.4 Two genes, CLN1 and CLN2, support services at Moorfields Eye Hospital (MEH) and from
encode for lysosomal proteases palmitoyl protein thioesterase
1 and tripeptidyl peptidase 1, respectively. Lysosomal Abbreviations: ERG, electroretinogram; jNCL, juvenile neuronal ceroid
membrane proteins of currently unknown function are lipofuscinosis; NCL, neuronal ceroid lipofuscinoses

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1120 Collins, Holder, Herbert, et al

the electrophysiology department database searching for in these two heterozygous patients were not identified. No
records with a diagnosis of Batten disease. genetic abnormality was identified in one patient. This
All patients had an extensive clinical examination, which patient also showed no vacuolated lymphocytes on peripheral
included visual acuity assessment, comprehensive ophthal- blood testing. The diagnosis of an atypical variant of jNCL
mic examination with dilated funduscopy and electrophy- was formed on the basis of characteristic clinical, neurophy-
siology. All patients underwent electrophysiological testing siological, and magnetic resonance imaging (MRI) findings.
based on the ISCEV standard, with variations in some EEG was reported as highly characteristic of Batten disease,
because of their young age, seven of which were performed at showing runs of large amplitude and slow wave and spike
our institution and two elsewhere. complexes.1 MRI scanning demonstrated cerebellar atrophy
In order to confirm the diagnosis, examination of a and white matter abnormalities. One patient, the oldest in
peripheral blood film for the presence of vacuolated the series, did not undergo molecular genetic testing.
lymphocytes and electron microscopy to observe for finger- Fingerprint inclusions were identified on blood film and skin
print inclusions were performed. In addition, patients biopsy in this patient. Leucocyte enzymes were assessed in
underwent molecular genetic testing to identify the common four of nine children, but no abnormality was detected. Of
1.02 kb deletion in CLN3. Four patients also underwent the four patients who underwent EEG testing, two had
testing for leucocyte enzymes to exclude infantile and late developed grand mal seizures and another absences.
infantile NCL.
Other investigations performed included magnetic reso- DISCUSSION
nance imaging (MRI) scans, skin biopsy, and an echocardio- This report details the phenotypic features in a series of
gram in one patient who had pre-existing cardiac problems,
patients with jNCL. The results of molecular genetic analysis
which showed stable mitral valve incompetence. and the key electrophysiological findings that facilitated early
Electroencephalograph (EEG) testing was performed in four
diagnosis of the disorder are described.
patients.
The age of onset of visual failure ranged from 4–8 years
All patients were referred to a developmental paediatrician,
(mean 6.4 years) with presentation to an ophthalmologist at
paediatric neurologist, clinical geneticist, family support
5.5–8.5 years (mean 7.3 years), which is comparable to an
service, and low vision aid services. In addition, they were
earlier series in which the peak incidence of visual failure was
given information regarding various support groups in the
6–7 years with a range of 4–10 years.2 Two of nine patients
United Kingdom such as the Batten Disease Association.
had developmental or behavioural problems before visual
deterioration; one child had behavioural problems noted at
RESULTS the age of 3 years—that is, 4.5 years before the onset of
General patient data and ophthalmic features are shown in visual failure and a second child had problems with speech
tables 1 and 2. Neurological features are summarised in and walking at the age of 3 years, 2 years before the onset of
table 3. visual failure. The time taken from presentation to an
The age at which diagnosis of jNCL was made ranged from ophthalmologist to the diagnosis of jNCL ranged from
6–11.5 years (mean 8.7 years). The time between presenta- 6 months to 4 years (mean 1.3 years). This time scale
tion to an ophthalmologist and diagnosis of jNCL ranged compares well in relation to other metabolic diseases such
from 6 months to 4 years (mean 1.3 years). Other provisional as adult Refsum syndrome; one recent study on adult Refsum
diagnoses had included cone/rod dystrophy, macular dystro- reported an average delay of 11 years between presentation
phy and retinal dystrophy. to an ophthalmologist and diagnosis.10
The results of electrophysiological tests are detailed in Overall, seven of nine patients presented with definite
table 4. Note the high prevalence of electronegative wave- symptoms and signs of visual failure/reduced visual acuity. In
forms under both scotopic and photopic conditions in the full two of nine patients there was documentation of behavioural
field ERGs. Pattern ERG, reflecting macular function, was problems and speech/walking difficulties at the age of
undetectable in five of six and showed residual activity in 3 years. It could not be ascertained therefore, whether the
only one eye of one patient. Examples of ERG recordings presenting feature in these two children was visual failure.
from three patients in this series are demonstrated in figure 1. Common additional ocular symptoms in this series were
Vacuolated lymphocytes on peripheral blood film testing night blindness and photophobia (table 2). Seven of nine
were present in eight of nine patients. Fingerprint inclusions patients had been provisionally diagnosed with other retinal
were observed in six of the eight in the blood film alone and disorders before the diagnosis of jNCL. These included cone/
in two on both blood film and skin biopsy. Five out of eight rod dystrophy, macular dystrophy, and retinal dystrophy. As
patients were homozygous for the 1.02 kb deletion on the most of these children present with visual failure it is quite
CLN3 gene on molecular genetic testing. Two patients were plausible that the cause may be attributed to another retinal
heterozygous for the same 1.02 kb deletion. Other mutations disorder rather than NCL until the clinical features progress;

Table 1 General patient data

Patient 1 2 3 4 5 6 7 8 9 Mean

Current age 10 13 9 8 16 13 6 10 17
Male/female F M F M M F M F F
Consanguineous parentage No No No No No No Yes No No
Age onset visual failure 7.5 5 4 7 7 8 5 6 8 6.4
Age at presentation to 5 (squint) 7.5 7 8 7 8 8.5 5.5 6.5 3 7.3
ophthalmologist (Duane)
8.0
Age at diagnosis 8.5 11 9 7.5 11.5 9 6 7 8.5 8.7
Presentation with visual Behaviour Yes Yes Yes Yes Yes Speech/walking Yes Yes
failure? problems age 3 problems age 3

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 Batten disease

Table 2 Ophthalmic features

Patient 1 2 3 4 5 6 7 8 9 Total

Visual acuity on presentation 6/60, 6/12 HM 6/60, 3/60 6/12,6/12 CF, 1/60 6/18, 6/18 Not fixing/following 6/60, 6/60 3/60, 3/60
to MEH
Symptoms reported
Poor night vision * * NR * NR * * NR NR 5/9
Photophobia NR * NR NR NR * NR * NR 3/9
Difficulty reading NR NR NR NR * NR NR * NR 2/9
Poor colour vision NR NR NR NR * NR NR NR NR 1/9
Presenting funduscopic signs
Bilateral bull’s Bilateral Bull’s eye Peripheral Optic atrophy, Normal fundus Subtle retinal changes Atrophic Normal fundus
eye maculopathy pigmentary maculopathy and pigmentary arteriolar on presentation maculopathy on presentation
and peripheral maculopathy arteriolar attenua retinopathy attenuation, macular and peripheral
atrophic and peripheral tion and peripheral pigmentary
retinopathy pigmentary pigmentary retinopathy
retinopathy retinopathy
Signs
Bull’s eye maculopathy  –  – ` ` , age 9 Subtle right – – 4/9
maculopathy*
Pigmentary maculopathy –  – `  – – – – 3/9
Atrophic maculopathy – ` – – ` – –  – 3/9
Peripheral atrophic retinopathy  ` – – – ` – – – 3/9
Peripheral pigmentary –  –   – * subtle  – 5/9
retinopathy
Bone spicules – ` – – – – – – ` 2/9
Arteriolar attenuation – `  `  – – – ` 5/9
Optic atrophy – ` – `  – – – ` 4/9
Overlooking/eccentric viewing – * – * * * – – – 4/9
Abnormal Ishihara * * * * * * ND * * 8/8
Constricted visual field * ND ND * * ND ND ND ND 3/3
Other Convergent Nystagmus Nystagmus Normal fundus Alternating exotropia, Normal fundus
squint on presentation nystagmus on presentation
Right Duane with
esotropia age 3
Other/initial diagnosis before Rod-cone Rod-cone Cone, cone-rod Retinal Cone dystrophy Non-organic Retinal dystrophy Macular dystrophy Non-organic
NCL dystrophy dystrophy or macular dystrophy visual loss visual loss
dystrophy

*Symptom/sign present. Fundal sign on first presentation. `Subsequent fundal feature/finding. –, Feature not present.
MEH, Moorfields Eye Hospital; NCL, neuronal ceroid lipofuscinoses; NR, feature not reported; ND, no data available.

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1121
1122 Collins, Holder, Herbert, et al

neurological/behavioural features develop; or the possibility

of Batten disease is raised by the ERG (table 3). Two of the

No neurological
symptoms/signs

Yes Grand Mal

nine patients were thought to have a functional visual
disorder initially as a reason for reduced visual acuity.
Bull’s eye maculopathy is commonly reported in the
literature on jNCL.1 11 12 However, only two of nine patients

Yes
9

–
–
presented with this feature, with a further two patients
No neurological subsequently developing a bull’s eye lesion. In one patient
symptoms/signs who initially had a normal fundal appearance this was
apparent one year after the development of visual failure. The
other patient had a pigmentary maculopathy at presentation,

Yes
No
followed by atrophic changes before eventually developing a
8

–
–
characteristic bull’s eye maculopathy (table 2). Two patients
had a normal fundal appearance on presentation and were
Walking with support
only, Reduced muscle
Communicates with

tone, Hyperreflexia
lower limbs, Ankle originally suspected of functional (non-organic) visual loss.
Developmental

This highlights that these changes may emerge with time and
single words

may not be apparent at the time of presentation with visual

regression,

Absences
failure. Spalton et al also noted the low number of patients
clonus

with a bull’s eye maculopathy at presentation.2

Yes
7

–
–
Visual field constriction was present in three of three
children in this series who underwent visual field testing.
No neurological
symptoms/signs

This may be an underestimate of the true number as testing

in young children can be difficult or unreliable. Four patients
had eccentric viewing, which would appear similar to the
No
No

feature described previously as ‘‘overlooking,’’ where children

6

–
–

held their eyes in a raised position when attempting to fixate

on a target. This was considered to be due to the relative
slurred speech, reduced
deep tendon reflexes in
coordination/rigidity,
Change in gait/poor

preservation of the superior peripheral retina.2

Learning difficulties,

The contribution of electrodiagnostic testing to diagnosis,

Yes, grand mal

further investigation and management of disease in the

lower limbs

paediatric ophthalmology population has previously been

dyslexia

3 years

described.13 The early electrophysiological tests performed in

Yes
10

many of these patients raised clinical suspicion of jNCL,

5

prompting further diagnostic tests to be performed. The ERG

Absences EEG requested

findings in this series included an unrecordable rod specific

behaviour/aggressive
Poor sleeping, erratic

ERG, an electronegative maximal response, reduced and

Learning difficulties

delayed cone flicker ERG, an undetectable pattern ERG, and

Difficulty writing

an abnormal photopic ON/preserved photopic OFF response,

Requested

in keeping with but extending those previously described.8

outbursts

1 year

Perhaps the feature most suggestive of jNCL is a markedly

reduced b:a ratio in the single flash photopic ERG with
4

additional a-wave delay. The electronegative ERG is consis-

Dyslexia, non-verbal

complex motor skills

assessment age 5 –

tent with the inner retinal localisation of the gene product for
learning disorder

temper/outbursts

CLN3.8 11 An electronegative ERG may also be observed in

Coordination of

Psychological

conditions such as X linked congenital stationary night

blindness and juvenile X linked retinoschisis,11 14 but the
difficult

combination of clinical features and other aspects of the

No
No

ERGs do not usually result in confusion.

3

–
–

In addition to the cognitive decline, progressive motor

difficulties, low IQ,

Problems standing
unsupported on 1
reduced cognitive

–, Not applicable/no data available. EEG, electroencephalogram.

skills: verbal and

disturbance and behaviour changes were noted in six of nine

patients. Two of nine patients were noted to have problems
leg, Slurred
non-verbal

with sleeping. These patients were both noted to have

Learning

speech
Neurological symptoms and signs

peripheral pigmentary or atrophic retinal changes (table 3)

No
No

In this series, 89% of patients (eight of nine) demonstrated

2

–
–

vacuolated lymphocytes and fingerprint inclusions on elec-

outbursts, Poor sleeping

tron microscopic testing (in two patients also on skin biopsy),

Aggressive behaviour/

a higher percentage than in previous series.2 15 Two patients

Poor coordination,
Feeding difficulties

Vague episodes

were found to be heterozygous for the 1.02 kb deletion of the

Slow learning

CLN3 gene; five others were homozygous and to date the

genetic mutation has yet to be identified in a further patient.
Diagnosis in this patient rested on the clinical findings,
No

neurophysiological and MRI testing, which were character-

1

–
–

istic of jNCL. The phenotype for patients heterozygous for the

Time after onset

common 1.02 kb deletion differs from that of patients

Age of onset

visual failure
Behavioural

homozygous for this deletion in that the course of the

Cognitive
Table 3

Seizures

disease is slower and some individuals may develop visual

Patient

Motor

EEG?

loss only into early adult life. This slower progression is

possibly because the unknown mutation on the other allele
does not abolish CLN3 activity completely.4 16

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Batten disease 1123

Table 4 Electrophysiology
Patient 1 2 3 4 5 6 7 8 9

Rod specific Undetectable NP Undetectable NP NP Severely NP

ERG Subnormal
Maximal Negative Negative Undetectable Negative Residual Negative Negative
response
Cone flicker Subnormal/ Delayed Undetectable Altered Undetectable Subnormal Subnormal,
ERG delayed waveform, delayed
preserved
amplitude
Photopic Reduced b:a Reduced b:a Undetectable Reduced b:a Reduced Reduced b:a Reduced b:a
ON/OFF 2ve ON, 2ve ON, NP 2ve ON, NP NP NP
Preserved OFF Preserved OFF Preserved OFF
PERG Undetectable Undetectable NP Undetectable Undetectable Undetectable Undetectable
RE, residual LE
VEP NP Delayed NP Delayed Residual NP Undetectable
Previous Said to be All ERGs Photopic ERGs Previous Previous ERGs The 30Hz flicker
ERG/ normal said to be done as EUA ERG age 7, 9 ERG waveform
comments elsewhere undetectable elsewhere elsewhere. First was in keeping
age 5 elsewhere age 7 – said to show with loss of ON
retinal cone, 2nd rod- response,
dystrophy cone dystrophy preservation of
OFF response

ERG, electroretinogram; PERG, pattern electroretinogram; VEP, visually evoked potential; EUA, examination under anaesthesia; NP, not performed.

In the early series by Spalton et al, diagnosis was often

delayed until the onset of seizures, with the delay in
diagnosis ranging from 1–9 years.2 None of their patients
had undergone standardised electrophysiological testing, and
our data suggest that early electrophysiology raises the
possibility of jNCL, which can then be confirmed by
molecular genetic testing. Many of the patients in the current
series had not developed seizures at the time of molecular
diagnosis.
Although jNCL is currently untreatable, it is important to
make the diagnosis at the earliest opportunity to inform
families and institute appropriate counselling. Planning for
the supportive care of the affected child (including the
family) may then be put into place. These patients should be
managed by a multidisciplinary team, including a paedia-
trician, paediatric neurologist, ophthalmologist, family doc-
tor, clinical geneticist, and a family support or equivalent
unit. Severe vision impairment registration and low vision aid
services are practical ways of providing help. Other measures
may include educational statementing to ensure local
authority provision of classroom support, especially impor-
tant if the child is to stay within the mainstream school
system. Families may gain much benefit from support groups
such as the Batten Disease Association.
In summary, a diagnosis of Batten disease (juvenile
neuronal ceroid lipofuscinosis) should be considered in
children of 10 years and under presenting with unexplained
visual loss in the presence either of a normal fundus or a
bull’s eye maculopathy. A low threshold should exist for
further investigation, particularly electrophysiology, which in
the present series contributed to earlier diagnosis than in
earlier reports, often enabling confirmatory laboratory and
genetic tests to be performed sooner than would otherwise
have occurred. A non-organic cause for visual loss should not
Figure 1 (A) ERGs recorded using a surface electrode on the lower be assumed until electrophysiology has demonstrated normal
eyelid. The upper trace is from patient 3, the lower trace from a normal function despite symptoms that suggest otherwise. A multi-
child. Note the reduction in the b:a ratio in the photopic single flash ERG; disciplinary approach has benefits to the management and
the delayed and reduced 30 Hz flicker ERG; and the profoundly
ongoing support of these patients.
electronegative bright flash dark adapted ERG (maximal). Broken lines
have been used to replace blink/eye movement artefact. (B) ERGs
.....................
recorded using corneal gold foil electrodes. The upper traces are from
patient 8; the middle traces are from patient 6 the lower traces are from Authors’ affiliations
a normal subject. The ERG characteristics are similar to those described J Collins, H Herbert, Moorfields Eye Hospital, London EC1V 2PD, UK
above with additional amplitude changes in the photopic ERG of patient G E Holder, Electrophysiology Department, Moorfields Eye Hospital,
8. Broken lines have been used to replace blink/eye movement artefact. London EC1V 2PD, UK

www.bjophthalmol.com
1124 Collins, Holder, Herbert, et al

G G W Adams, Strabismus and Paediatric Service, Moorfields Eye 7 Mole SE. The neuronal ceroid lipofuscinoses (NCL)—a group of lysosomal
Hospital, City Road, London EC1V 2PD, UK diseases come of age. Brain Pathol 2004;14:70–6.
8 Mantel I, Brantley MA Jr, Bellman C, et al. Juvenile neuronal
Correspondence to: Miss Gillian G W Adams, Strabismus and ceroid lipofuscinosis (Batten disease) CLN3 mutation
(Chrom 16p11.2) with different phenotypes in a sibling pair
Paediatric Service, Moorfields Eye Hospital, City Road, London EC1V and low intensity in vivo autofluoresence. Klin Monatsbl Augenheilkd
2PD, UK; gill.adams@blueyonder.co.uk 2004;221:1–4.
9 Marshman WE, Lee JP, Jones B, et al. Duane’s retraction syndrome and
Accepted for publication 16 May 2006 juvenile Batten’s disease—a new association? Aust N Z J Ophthalmol
1998;26:251–4.
10 Claridge KG, Gibberd FB, Sidey MC. Refsum disease: the presentation and
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