American Journal of Medical Genetics 57:144-149 (1995)
Childhood Neuronal Ceroid-Lipofuscinoses
in Argentina
Ana Lia Taratuto, Maria Saccoliti, Gustavo Sevlever, Victor Ruggieri, Hugo Arroyo, Maria Herrero,
Mario Massaro, and Natalio Fejerman
Instituto de Inuestigaciones Neurologicas Raul Carrea, Fundacidn de Lucha Contra las Enfermedades Neurologicas en
la Infancia (A.L.T., M.S., G.S.), and Hospital Nacional de Pediatria Juan P. Garrahan (A.L.T., V.R., H.A., M.H.,
M.M., N.F.), Buenos Aires, Argentina
We report on 30 cases of neuronal ceroid
lipofuscinoses (NCL), mainly diagnosed in
1985-1993 in Argentina, whose population is
predominantly of European descent. 'henty-
four cases were late infantile Jansky-
Bielschowsky (LINCL) and 6 were juvenile
Spielmeyer-Vogt (JNCL). Sex ratio was fe-
male:male, 20:lO. Age range and mean at
onset and at diagnosis for the LINCL cases
were 1 4 years, mean 3.1, and 2-11 years,
mean 5.5, and for the JNCL cases, 5-9 years,
mean 7, and 9-18 years, mean 13, respec-
tively. Cases were referred for biopsy after
neurological examination, and most in-
cluded complete electrophysiological [elec-
troencephalography (EEG) with photic
stimulation, electroretinography (ERG),
and visual-evoked potential (VEP)], neu-
roimaging, and neurometabolic investiga-
tion. NCL was the first suspected clinical
diagnosis, followed by mitochondria1 en-
cephalopathy in some cases of recent onset.
Except for 1 case, clinical findings were
homogeneous in LINCL, characterized by
refractive epilepsy, mental regression and
progressive deterioration, ataxia, myoclo-
nia, and visual loss. Abnormal VEP, ERG,
and EEG, with polyphasic high-voltage
spikes when photic stimulation was per-
formed at low frequency, were observed. Vi-
sual impairment and retinitis pigmentosa
were early manifestations in 416 JNCL, fol-
lowed by mental abnormalities, motor dete-
rioration, and myoclonic jerks, while 2/4 fol-
lowed an atypical course. In both variants
inheritance was autosomal-recessive. Five
out of 27 families had more than 1 affected
Received for publication July 5, 1994; revision received Sep-
tember 30, 1994.
Address reprint requests to Ana Lia Taratuto, M.D., Instituto
de Investigaciones Neurologicas Radl Carrea, FLENI, Departa-
mento de Neuropatologia, Montafieses 2325, 1428 Buenos Aires,
Argentina.
0 1995 Wiley-Liss, Inc.
~~~
member, 3 of whom were included in our se-
ries. Diagnosis was initially performed in
conjunctival biopsy in 3 cases, skin in 5,
muscle in 17, and brain in 5, though most
cases had a concomitant biopsy from an-
other tissue including nerve, and there was
a single brain autopsy. In the LINCL vari-
ant, storage material was mainly curvilin-
ear, also exhibiting dense areas and
electron-lucent vacuoles in 1 case. In addi-
tion to fingerprint profiles in 4/6 cases,
JNCL biopsies presented curvilinear pro-
files in a skin biopsy in 1 case, and electron-
lucent vacuoles in 2 cases in a muscle and
brain biopsy coexisting within the same in-
clusion, with the curvilinear profiles sur-
rounded by a unit membrane, while the
other 216 had granular osmiophilic inclu-
sions with poorly defined rectilinear areas.
The purpose of this report is to describe
NCL in a country mainly populated by Eu-
ropean descendants, in order to contribute
data for further collaborative research.
0 1995 Wiley-Liss, Inc.
KEY WORDS: ceroid-lipofuscinoses, NCL,
lipid storage disease, Haltia-
Santavuori disease, Jansky-
Bielschowsky disease, Batten-
Spielmeyer-Vogt disease
INTRODUCTION
Neuronal ceroid-lipofuscinoses (NCL) are among the
most frequent neuronal storage diseases in childhood,
with a n autosomal-recessive inheritance pattern and
reported incidence of 1 in 25,000 per liveborn infants
[Zeman, 19741, although the infantile variant is more
frequent in Finland, with a n incidence of 1 in 20,000
[Jarvela, 19911. The rare adult type, Kufs disease, may
also present a dominant inheritance pattern.
Three main clinicopathological childhood forms or
major syndromes have been recognized, based on age at

onset, clinical course, and morphological observations:
CLN1, infantile NCL (INCL) or Santavuori-Haltia dis-
ease; CLN2, late infantile NCL (LINCL) or Jansky-
Bielschowsky disease; and CLN3, juvenile NCL (JNCL)
or Spielmeyer-Vogt or Batten disease [Santavuori, 1973;
Haltia et al., 1973; Hagberg et al., 1968; Carpenter et
al., 1972; Kohlschutter et al., 19931, although variability
in clinical and pathological findings has been reported
[Goebel et al., 1976; Libert e t al., 1982; Wisniewski et
al., 1988,1992a;Goebel, 19931. Additional atypical vari-
ants [Wisniewski et al., 19871 or minor syndromes have
been described, and a more extensive classification of
NCL has been proposed [Dyken, 1988,19891.
In spite of intensive research, a specific biochemical
defect has not yet been identified. Elevated dolichols
have been reported in both urine and brain of NCL pa-
tients, although a consistent test could not be obtained
[Ng Ying Kin and Wolfe, 1982; Pullarkat and Reha,
1982; Bennett e t al., 19851. As dolichols are involved in
glycoprotein synthesis, their metabolism has been ex-
tensively investigated, and defects in the processing of
N-linked and O-linked oligosaccharides in NCL glyco-
proteins have been reported [Wisniewski and Szuman-
ska, 1986; Krusius et al., 19861.
Increased immunoreactivity with antibodies against
certain amyloid P-protein precursor domains in NCL
brains has been found, probably related to abnormal
protein processing [Wisniewski et al., 1988, 1990a,b,
1992bl.
More recently, it has been reported that subunit c of
mitochondria1 ATP synthase is a significant component
of protein in the storage bodies of the ovine, late infan-
tile, and juvenile forms as well as in the adult form
[Palmer et al., 1992; Lake and Hall, 19931, but not in
the infantile form.
CLNl has been assigned to chromosome area lp32
[Jarvela, 19911, and CLN3 to chromosome 1 6 ~ 1 2
[Eiberg et al., 19891,allowing prenatal and carrier diag-
nosis, but the CLNB gene is still under active research.
Given the limitations of current biochemical markers
and CLNB chromosomal mapping, electron microscopy
still remains a valuable tool for diagnostic purposes.
Our present aim is to contribute data for collaborative
genetic andlor biochemical studies, a s well as for fur-
ther characterization of atypical variants, through the
report of 30 cases of NCL in Argentina, mostly diag-
nosed in 1986-1993, except for 5 cases which were
studied earlier.
MATERIALS AND METHODS
Clinical Data
We reviewed clinical data available on 30 NCL cases,
biopsy-confirmed, most of them diagnosed between
1986-1993, except for 5 cases which were studied in the
1970s, 2 CLNB and 3 CLN3. A further case, not in-
cluded in this review, was suspected to be CLNl but
had no follow-up data.
Fifteen cases have been followed up a t the Garrahan
Childrens’ Hospital and the rest were biopsy referrals
from other neuropediatric hospitals. Although the eth-
nic distribution is similar to the Argentinian popula-
tion, which is mainly of Spanish and Italian ancestry,
Childhood NCL in Argentina 145
there were 2 French (sibs), 1German, and 1Ashkenazi
patient.
Cases were classified mainly on the basis of clinical
manifestations, age a t onset and a t diagnosis, and elec-
tron microscopy observations [Wisniewski et al., 1988,
1992a; Kohlschiitter et al., 19931.
Patients were evaluated by neurologic examination,
neurometabolic investigation, electrophysiological stu-
dies (EEG with photic stimulation, ERG, and VEP),
and neuroimaging [computed tomography (CT) and/or
magnetic resonance imaging (MRI)].
Pathology
Biopsies included 5 from brain (3 LINCL, 2 JNCL);
18 from muscle (16 LINCL, 2 JNCL); 5 from nerve (4
LINCL, 1JNCL); 2 from conjunctiva (2 LINCL); and 10
from skin (8 LINCL, 2 JNCL). There was also 1 brain
autopsy.
Light microscopy. Formalin-fixed frozen sections
of brain biopsies and the autopsy were observed under
fluorescent light and stained for Sudan black B, PAS,
and Bielschowsky. Paraffin sections were stained with
hematoxylin-eosin, Nissl, Luxol Fast Blue (LFB), Kin-
youn’s carbol fuchsin for lipofuscin-ceroid, Sudan black
B, and PAS before and after chloroform-methanol 1:l.
Muscle biopsies were frozen in isopentane in liquid
nitrogen. Routine histochemical and histoenzymologi-
cal techniques including acid phosphatase were per-
formed in cryostat sections. Autofluorescence was also
investigated.
Nerve biopsies were fixed in 4% paraformaldehyde,
and half of the material was embedded in paraffin. Sec-
tions were stained with hematoxylin-eosin, PAS, and
LFB. The other half was postfixed in 1% osmium tetrox-
ide, for teasing under a stereoscopic microscope.
Electron microscopy. Muscle was fixed in 4%
glutaraldehyde in cacodylate buffer; conjunctiva, skin,
nerve, and brain were fixed in 2% glutaraldehyde in ca-
codylate buffer for 3 hr, washed in buffer, postfixed in
osmium tetroxide, dehydrated, and embedded in epon.
Semithin sections were stained with methylene blue,
and ultrathin sections with Reynolds, and then exam-
ined under a Siemens Elmiskop 101 or a Zeiss 109 elec-
tron microscope.
RESULTS
Clinical Findings
Age a t onset and sequence of signs and symptoms
were gleaned from clinical records in all cases, although
on occasion available data were limited to findings
before diagnostic biopsy, so that the exact age a t pre-
sentation of each sequential symptom could not be ac-
curately determined.
Sex ratio was female:male, 20:lO. Three pairs of sibs
from 3 different families were included in this series; in
addition, 2 cases had affected sibs (not included). Thus,
out of 27 families, 5 (18.5%) had more than 1 affected
member.
LINCL clinical findings were relatively homogenous,
with onset between 1-6 years of age, mean 3.1 years
(Table I), the youngest case diagnosed being a n affected
146 Taratuto et al.
TABLE I. Age at Onset and at Biopsy Diagnosis in 30 Pediatric Cases of NCL
Age at biopsy diagnosis
Age.-at onset (years) (years)

Variant Cases Range Mean ? SD Ranee Mean ~

Late infantile 24 1-6 3.1 5 3.14 2-11 5.5 -c 5.59

Juvenile 6 5-9 7.0 ? 6.67 9-18 13.0 2 12.84
Total 30

sib, also included. Refractive epilepsy was the initial
and most remarkable feature, followed by mental re-
tardation, progressive deterioration, ataxia, dementia,
myoclonia, and late visual impairment. Electrophysio-
logical tests included large somatosensory (SEP) and
VEP, which became unrecordable with progressive dis-
ease. EEGs showed polyphasic high-voltage spikes in
posterior regions when photic stimulation was per-
formed a t low frequency. CT scan andlor MRI showed
cerebral and cerebellar atrophy.
A single boy with onset a t age 6 years was rather
atypical, starting with behavioral changes, difficulty in
learning, and dysarthria for 2.6 years, with normal CT-
scan/MRI and EEG during this period, followed by
tremor, gait unsteadiness, partial complex seizures,
and myoclonia. At the time of biopsy, a t age 9.5 years,
dementia, difficulty in swallowing, and severe ataxia
were evident. VEP and fundus oculi were still normal,
and there was no positive spikes in EEG during photic
stimulation. MRI showed severe cerebral and cerebel-
lar atrophy, as well as hypointensity in basal ganglia.
JNCL onset was between ages 5-9 years, mean 7,
with visual impairment a s the presenting and most
striking abnormality in 416 cases, which had been the
sole recorded symptom for 4, 5, and 7 years in 3 pa-
tients. Retinitis pigmentosa and decreased or abolished
VEP and ERG were observed, while EEG, though ab-
normal, only showed positive spikes during photic stim-
ulation in 2 cases. Mental abnormalities were first
interpreted as secondary to visual impairment. However,
later neurological compromise was characterized by
motor deterioration, pyramidal and extrapyramidal
and cerebellar signs, and myoclonic jerks, as well a s
generalized seizures. CT brain scanning and MRI dis-
closed only moderate cerebral and cerebellar atrophy
at diagnosis (Table 11).
Two sisters presented a n atypical course. The older,
age 15 years, with onset a t age 9 years, had seizures,
myoclonic jerks, intellectual deterioration, cerebellar,
pyramidal, and extrapyramidal symptoms and signs,
and late visual loss. At brain biopsy in 1976 (6 years af-
ter onset), retinitis pigmentosa and abnormal EEG,
with high-voltage spikes during photic stimulation,
were evident, while a pneumoencephalogram and a CT
brain scan showed moderate cortical atrophy, slight
ventricular enlargement, and cerebellar atrophy. At
brain biopsy, neither characteristic fingerprint nor
curvilinear profiles could be discerned, but granular os-
miophilic inclusions surrounded by a unit membrane
with poorly defined rectilinear areas were observed.
Her 9-year-old sister developed myoclonia and general-
ized seizures, and also had retinitis pigmentosa, but no
evident visual impairment a t onset. A skin biopsy
showed similar inclusions.
Pathology
Diagnosis was initially performed in conjunctival
biopsy in 3 cases, skin biopsy in 5, muscle biopsy in 17,
and brain biopsy in 5, although most had a concurrent
biopsy from a further tissue, and there was 1 brain
autopsy.
Brain biopsy (prefrontal right). Three from
LINCL were performed 1 year, 1 year 6 months, and 3
years 6 months after onset, and 2 from JNCL were per-
formed 6 and 11 years after onset.
Light microscopy. Lesion severity varied from one
specimen to another, with marked neuronal loss in
cases of longer survival. Neurons, mainly in the second,
third, and fifth layers showed distended, ballooned cy-
toplasm containing granular material strongly stained
in frozen and paraffin sections with Sudan black B and
PAS, and faintly stained by LFB, even after exposure to

TABLE 11. Clinical Signs and Symptoms Recorded at Biopsy”

LINCL JNCL
Seizures Total: 24/24 616
Myoclonic: 19/24 516
Toniclonic: 15/24 416
Partial: 5/24 116
Visual impairmenfloss 4/24--NA. 1/24 516
Motor: ataxia 18124-NA: 1/24 516
Dementia 19/24-NA 1/24 516
EEG photic stimulation+ 13124-NA 11/24 316
TCIMRI Corticakerebellar atrophy 11/24--NA. 10124 316 -N A 216
* NA, data not available.
 Childhood NCL in Argentina 147

chloroform-methanol. Granules were acid-fast-positive

and autofluorescent (yellowish-green). There was a
slight increase in microglia and reactive astroglia, with
a few PAS-positive granules.
Brain autopsy. One LINCL was performed 6 years
after onset.
Macroscopic findings. This specimen from a 9-year-
old girl weighed 400 g. There was severe diffuse corti-
cal atrophy, with extreme bilateral symmetrical IIIrd
and IVth ventricular dilatation. There was also evident
cerebellar atrophy.
Light microscopy. There was severe and extensive
cerebral cortical neuronal depletion, with diffuse spongi-
ness and astrocytic hyperplasia. Remaining ballooned
neurons contained PAS, LFB, Sudan black B-positive,
and autofluorescent granules. Myelinated fiber loss
was obvious, mainly in white matter. Severe cerebellar
cortical atrophy manifested extensive depletion of
granular cells and Purkinje cells with gliosis. Remain-
ing neurons were ballooned, containing granular mate-
rial. Extensive compromise of basal ganglia, brain
stem, pons, and medulla neurons was observed.
Etectron microscopy. LINCL specimens, including 1
brain autopsy, had characteristic curvilinear inclusions
in neuronal perikaryon and processes, a s well a s in en-
dothelial cells (Fig. la). One JNCL biopsy showed fin-
gerprint inclusions, some of which had electron-lucent
vacuoles. Another JNCL biopsy (with atypical onset
and late visual loss) had granular osmiophilic inclu-
sions surrounded by a unit membrane, with poorly de-
fined rectilinear areas (Fig. 3).
Muscle biopsy. Light microscopy. Muscle biop-
sies showed a variable amount of intermyofibrillar and
subsarcolemmal acid phosphatase-positive autofluores-
cent granules.
Electron microscopy. In LINCL, ultrastructurally
curvilinear inclusions limited by a unit membrane (Fig.
lc) were observed in all 16 biopsies. In JNCL, finger-
print inclusions also limited by a unit membrane were
observed in 2 cases, 1also showing curvilinear profiles,
granular material, and electron-lucent vacuoles.
Nerve biopsy. Light microscopy. There was
preservation of myelinated fiber density in 315 cases
studied, whereas in 2/5 (1 LINCL and 1 JNCL) there
was mild myelinated fiber loss.
Electron microscopy. Curvilinear inclusions were
only observed in a single LINCL, mainly in endothelial
Fig. 1. a: Inclusions surrounded by a unit membrane containing
cells; diagnosis was performed in the remainder in con- curvilinear profiles within a neuron from a brain biopsy. LINCL,
comitant muscle biopsies and in a brain biopsy. One X40,OOO. b: Curvilinear inclusions with an electron-lucent vacuole in
case with myelinated fiber loss, but without evident in- an endothelial cell from a conjunctival biopsy. LINCL, X24,OOO. c:
Subsarcolemmal curvilinear inclusions from a muscle biopsy. LINCL,
clusions, showed intraaxonal concentric lamellar pro- X24,OOO.
files. The only JNCL case observed showed myelinated
fiber loss, while fingerprint inclusions were evident in served within the same unit membrane. Both conjuncti-
Schwann cells (Fig. 2b), pericytes, and endothelial cells. val biopsies proved positive, as well as 6/8 skin biopsies.
Conjunctiva and skin biopsies. Electron mi- In JNCL, fingerprint inclusions were observed in
croscopy. Inclusions were disclosed in epithelium and both skin biopsies (Fig. 2a), 1 of which also showed fo-
eccrine sweat glands in skin, and in endothelial cells cal areas of curvilinear profiles within the same unit
and nerve fascicles within Schwann cells, in both skin membrane (Fig. 2c).
and conjunctiva.
In LINCL, curvilinear inclusions were observed in all DISCUSSION
positive cases, in 1 of which (conjunctiva) dense areas In this retrospective review of 30 cases of childhood
and/or electron-lucent vacuoles (Fig. l b ) were also ob- NCL, 24 were CLN2 and 6 were CLN3, a ratio a t vari-
148 Taratuto et al.
Fig. 2. a: Fingerprint inclusions surrounded by a single unit mem-
brane within a n endothelial cell from a skin biopsy. JNCL, X80,OOO.
b: Fingerprint inclusions in a Schwann cell from a nerve biopsy.
JNCL, X24,OOO. c: Fingerprint and curvilinear profiles within the
same inclusion in a pericyte from a skin biopsy. JNCL, X40,OOO.
ance with that described in other series where juvenile
cases were far more frequent than late infantile cases
[Wisniewski et al., 1992al. The question is whether the
ratio in our series corresponds to the actual profile, or if
there is some sort of bias, perhaps because juvenile
cases are underrepresented at pediatric hospitals. The
age at onset, range, and mean closely agree with these
variants, but a s we have not systematically performed
lymphocyte pellet studies or rectal biopsies, which are
useful for differential diagnosis, showing curvilinear
Fig. 3. Granular osmiophilic inclusions with poorly defined recti-
linear areas in a neuron from a brain biopsy. JNCL, X40,OOO.
profiles in CLN2 and fingerprint profiles in CLN3, we
cannot rule out that some of the cases considered by us
a s CLN2 on the basis of age and clinicopathological a s
well a s biopsy (skin, muscle or conjunctiva) data, may
correspond to the CLN3 variant. Accordingly, the living
LINCL patients should undergo a complementary lym-
phocyte pellet study before genetic evaluation.
I n a recent report on NCL from Italy [Cardona and
Rosati, 19941, the incidence of LINCL was also higher
than that of JNCL (37/18 cases). Whether our data are
in some way related to these, since most Argentinians
have Italian or Spanish ancestors, needs further re-
search. So far, we are unable to provide epidemiological
figures, despite the fact that our hospital is the largest
of its kind and receives referrals from throughout the
country, since, in all likelihood, cases are not biopsy-
confirmed in distant areas lacking local facilities.
Although NCLl has a low incidence worldwide, ex-
cept in Finland, we think that there is little awareness
of this variant in our country, so it probably remains
underdiagnosed.
A single case of a n 8-month-old male referred to us
in 1979, with a presumptive clinical diagnosis of INCL,
whose skin biopsy showed osmiophilic granular cyto-
plasmic inclusions surrounded by a unit membrane
(although granules were slightly coarser than those
commonly described), was disregarded due to lack of
follow-up and, thus, insufficient clinicopathological
data.
There is a n evident delay in diagnosis in our series,
reaching 2.5 years for NCL2 and 6 years for NCL3, al-
though 3 cases of the latter variant had been diagnosed
before MRI was available. In fact, 3 of the NCL3 cases
described here may have long remained underdiag-
nosed due to 4 , 5 , and 7 years of visual impairment and
retinitis pigmentosa.
An atypical LINCL case with onset at age 6 years had
a history of 2.6 years of behavioral changes, difficulties
in learning, and dysarthria. Although there was neuro-
logical deterioration later, VEPs were still normal, and
photic spikes at EEG could not be elicited a t the time of
biopsy (9.5 years). In this connection, Santavuori et al.
[1991a, bl reported a series of 5 patients with a variant

type of Jansky-Bielschowsky disease with onset mani-
festing mental and slight motor symptoms, and pre-
senting with late abnormal VEP and photic spikes.
Likewise, a JNCL case proved atypical, presenting
with late visual loss and granular osmiophilic deposits,
with poorly defined rectilinear areas surrounded by a
unit membrane at brain biopsy a t age 15 years, while
her younger sister with onset at age 9 years with gen-
eralized seizures and myoclonia, but not visual impair-
ment, had similar findings at skin biopsy, recalling the
granular osmiophilic deposits (GROD) described by
Carpenter et al. [1973]. Overall clinical variability in
our series was lo%, considerably lower than that re-
ported for larger populations [Wisniewski et al., 19881.
As regards biopsies other than brain, which were per-
formed in the 1970s, muscle was consistently positive,
followed by skin and conjunctiva, while nerve was ap-
parently less o r later involved, a s shown by concomi-
tant biopsies. Despite pathological variability in some
cases, characteristic inclusions for each variant pre-
dominated widely. In muscle, in a single JNCL biopsy
over 18 muscle biopsies in the entire series, in addition
to fingerprint, curvilinear profiles, granular material,
and electron-lucent vacuoles were also observed in a
few inclusions. In skin and conjunctiva, variability was
limited to 2/10 positive biopsies, occasionally showing
within the same unit membrane, curvilinear, dense
areas and electron-lucent vacuoles in 1 late infantile
case, and fingerprints as well a s curvilinear profiles in
a juvenile case.
Present findings will no doubt prove useful to genetic
studies on each NCL variant, particularly in the late in-
fantile form of the disease.
ACKNOWLEDGMENTS
The authors thank Drs. L. Benasayaz, R. Caraballo,
J. Castafio, N. Chamoles, C. Estol, 0. Gershanik, S.
Gonorasky, J. Grippo, and S. Tenembaum for biopsy
referrals.
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