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Clinical and magnetic resonance imaging findings in batten disease Analysis of the major mutation (1.02-kb deletion)

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Clinical and Magnetic
Resonance Imaging Findings
in Batten Disease: Analysis
of the Major Mutation
(1.OZ-kb Deletion)
Irma Jarvela, MD, PhD,* Taina Autti, M D , t $
Sirkka Lamminranta, MSc,? Laura Aberg, M D , t
Raili Raininko, MD,$ and Pirkko Santavuori, MDt
A total of 36 patients with Batten disease (juvenile-onset
neuronal ceroid lipofuscinosis), homozygous or heterozy-
16~11.2-12.1 by the random linkage approach [2].
Since the cloning of the CLNS gene, four different
mutations have been described, the I .02-kb deletion in
genomic DNA being present in 80% of affected chromosomes [3]. In Finland, which has a population of 5
million, altogether 183 Batten patients have been diagnosed so far. The prevalence of the 1.02-kb deletion is
the highest reported, representing 90% of all Finnish
CLNS chromosomes [4].
The purpose of this study was to investigate all Batten disease patients followed up for 25 years who had
undergone brain magnetic resonance imaging (MRI) to
find out if any important clinical features correlated
with the homozygous or heterozygous presentation of
the 1.02-kb deletion.
gous for the major mutation, a 1.02-kb deletion, in the
CLN3 gene, were studied to relate their genotype to their
clinical phenotype. The onset of visual failure and epilepsy was highly concordant in both groups. Great interand intrafamilial heterogeneity was demonstrated in the
development of mental and physical handicap and in
magnetic resonance imaging findings among both homozygous and heterozygous patients. The 1.02-kb deletion in homozygous form was always associated with
mental and physical handicap, whereas the heterozygous
phenotype could be extremely benign without affecting
the intellectual level of the patient. Our data suggest that
genetic background, modifying genes, and environmental
factors all influence the final phenotype of Batten disease.
Jarvela I, Autti T , Lamminranta S, Aberg L, Raininko R,
Santavuori P. Clinical and magnetic resonance imaging
findings in Batten disease: analysis of the major mutation
(1.02-kb deletion). Ann Neurol 1997;42:799-802
Batten disease or juvenile-onset neuronal ceroid lipofuscinosis (JNCL; gene symbol CLN3) is the most
common neurodegenerative disorder of childhood in
western countries and is characterized by visual failure,
epilepsy, and psychomotor deterioration [ 11. Ceroid
and lipofuscin-like lipopigments accumulate in the
neural and nonneural tissues of the patients, although
symptoms reflect only disease in the central nervous
system. Batten disease is inherited as an autosomal recessive trait and was localized to human chromosome
From the *Laboratory of Human Molecular Genetics, National
Public Health Institute, TDepartment of Paediatric Neurology,
Children’s Hospital, University of Helsinki, and $Department of
Radiology, University of Helsinki, Helsinki, Finland; and SDepartment of Diagnostic Radiology, University of Uppsala, Uppsala,
Received Feb 11, 1997, and in revised form Apr 23. Accepted for
publication Jun 13, 1997.
Address correspondence to Dr Jarvela, Laboratory of Human Molecular Genetics, Mannerheiinintie 166, 00300 Helsinki, Finland.
Subjects and Methods
The study group consisted of all Batten disease patients (n =
36) in whom brain MRI at 1.0 T had been performed. The
patients were followed up since 1971 at Children’s Hospital,
University of Helsinki. Seven families had 2 to 3 affected
siblings. All patients had vacuolated lymphocytes in repeated
examinations and a typical electron microscopic finding on
rectal biopsy [5]. All, except 5 patients, showed macular degeneration at the time of confirmation of the diagnosis. Electroretinography (ERG) was stopped by that time in most
patients, or in a few, 6 to 12 months later. Typical retinal
degeneration with pigment aggregations became visible during the second decade. All showed optic atrophy. Clinical
data on each patient were recorded at the time of diagnosis
and annually at each subsequent clinical visit. The parameters used in the analysis of clinical phenotypes included neuropsychological and neurophysiological examinations (electroencephalogram, ERG, and sensory and visual evoked
potentials). The 1.02-kb deletion was identified by a polymerase chain reaction-based minisequencing test as described
previously 141. The study was performed with the approval
of the Ethics Committee of Children’s Hospital at Helsinki.
Neurological scoring of the disease was performed by using a scale for the evaluation of motor function including
gross motor performance, balance, coordination, speech, and
intelligence [6]. Each item was scored from zero to four, the
higher the score the greater the severity. At the beginning of
follow-up, the Wechsler Intelligence Scale for Children, Revised (WISC-R) was used in neuropsychological scoring.
Since 1986, the neuropsychological test battery, which was
specifically developed for JNCL patients, was available. The
battery, including the verbal WISC-R, was adapted from Luria’s neuropsychological test [7] and was modified for the
visually handicapped.
MRI was performed with an imager operating at 1.0 T
and was repeated at 2- to 6-year intervals in 12 patients. The
MR images of 47 healthy volunteers served as controls [S].
After visual evaluation, the signal intensity of the brain was
measured. Ratios benveen gray and white matter were calculated and those different from those ratios of controls by
more than t 2 S D were considered pathological [9]. Atrophy
of the brain was graded as mild, moderate, or severe [ 101.
Copyright 0 1997 by the American Neurological Association
Two different types of disease progression could be
distinguished in the development of extrapyramidal
signs in homozygous patients; that is, parkinsonian
signs were noticed in 8 of 27 (30%) of patients between 12 and 15 years of age (mean, 13.5 years) and in
6 of 27 (22%) patients between 17 and 29 years of age
(mean, 21.6 years). Six (22%) additional patients
showed good motor performance between 14 and 22
years of age. In 7 children, no definite conclusion
could be drawn, because 5 of them were younger than
13 years of age. Six of 8 children with early onset extrapyramidal signs became wheelchair dependent at a
mean age of 16.4 years (range, 15-23 years), and 4 of
12 with late-onset parkinsonian signs between 22 and
26 years (mean, 24.3 years). One homozygous male
patient, age 31, still walks and speaks clearly. Extrapyramidal signs have been noticed in only I heterozygous
patient at 19 years of age. Onset of speech failure correlated rather well with onset of parkinsonian signs.
Signs of truncal ataxia became evident in most homozygous and heterozygous patients before 15 years of
age, and interfamilial and intrafamilial variation was
less evident than with the other symptoms. Greatest
intrafamiliar variation was demonstrated between 2 sisters homozygous for the 1.02-kb deletion. The younger
became blind at the age of 11, wheelchair bound at the
age of 15, had severe epilepsy and psychotic symptoms,
and died at the age of 18 years. Her older sister became
blind at the age of 20, wheelchair bound at the age of
23, and is now 26 years old with a milder course of the
Behavioral problems (aggressive bursts and depressive behavior) were noticed in 14 of 27 (52%) homozygous patients. In addition, 6 of them had psy-
Twenty-seven patients including 5 sibling pairs were
homozygous and 9 patients including 2 sibling pairs
were heterozygous for the 1.O2-kb deletion.
Visual failure was noticed at a mean age of 5.8 years
(range, 4-10 years) in all patients. The patients became practically blind between 6 and 20 years of age.
The onset and progression of visual failure varied between the siblings in both homozygous and heterozygous groups.
In 25 of 27 (92%) homozygous patients, the onset
of epilepsy occurred between the ages of 8 and 13 years
(mean, 11.2 years; range, 6-16 years), and in 5 of 9
(55%) heterozygous patients between 8 and 12 years of
age (mean, 10.2 years). Two homozygous patients
(8%), ages 7 and 11, and 4 (45%) heterozygous patients, from 6 to 30 years of age, have not so far had
epileptic seizures.
The results of neurological and MRI findings are
presented in the Table; 21 of 27 (78%) homozygous
patients were mentally normal, 4 (15%) were subnormal, and 2 (7%) were mentally retarded, between 5
and 10 years of age when diagnostic examinations were
performed. A mental decline (IQ lowering 2 10 points)
was noticed in 13 patients (48%) before 10 years of
age and in 11 patients (41%) between 1 1 and 23 years.
Greatest decline in motor functions and intelligence
took place between 11 and 15 years of age, whereas
loss of speech developed after I 5 years of age in homozygous patients (see Table). Among the heterozygotes, mental decline occurred at a mean age of 12.
Neurological and MRI findings were milder among the
heterozygotes (see Table). Two heterozygous male patients, ages 15 and 29, had IQs of more than 130.
Table. Neurologicul and MRI Findings in the Patients with jNCL Hornozygous or Heterozygous f i r the I.02-kb Deletion
Neurological Findings"
Motor Functions
Number of
Age (yr) Examinations"
Homozygous patients
11-15 12
Heterozygous patient5
Med Range
5 (8) 3-9
0 (2)
MRI Findings
Number of
Mean Med Range Mean Med Range Examinations
0 (1) 0-1
2 (3)
Atrophy (Yo) Matter Ratios (Yo)
4 (33%)
317 (43)'
2 (66%)'
I (So/,)
"Neurological scores: motor fiinctions, max 12; speech, max 4;intelligence, max 4.The higher the score, the greater the symptoms.
"Eight homozygous and 4 heterozygous patients were examined twice at 2- to 6-year intervals.
T h e MR images of some patients could not be measured.
'Same patient, at the ages of 24 and 29 years.
MRI = magnetic resonance imaging; JNCL, = juvenile-onset neuronal ceroid lipofuscinosis; med = median; max
Annals of Neurology
Vol 42
No 5
November 1997
Fig. (A) The magnetic resonance (MR) image (pin echo 2,500/90) of u 29-year-old Batten disease patient heterozygous for the
1.02-kb deletion shows normal signal intensities of gray und white mutter and only a few slightly enlarged sulci. (B) The M R image of u 15-year-old Butten diseuse patient homozygous for the I.02-kb deletion shows a moderately enlarged third ventricle (open
arrow) und cerebral sulci, and the thulami are hypointense rehtive to the udjacent white mutter (white arrow).
chotic-like symptoms and 6, hallucinations. Similar
behavioral problems were seen in 3 of 9 (33%) heterozygous patients. The mean age of death among homozygotes was 23.6 years (range, 10-28 years). These
patients were totally bedridden at 6 months (range,
0-12 months). No patient was in a vegetative state.
The MRI findings of compound heterozygotes were
usually milder than those of homozygotes (see Table;
Fig). Mild to moderate cerebral atrophy was found in
19 of 49 (39%) examinations. The signal intensity of
periventricular white matter was increased and fell outside the range of + 2 SD in 15 patients (14 homozygous and 1 heterozygous for the 1.O2-kb deletion).
Pathological signal intensity ratios between deep gray
matter and peripheral white matter were found in 10
examinations of the homozygous but never in heterozygous patients (see Table). A great variation in the MRI
findings is demonstrated between homozygous and
heterozygous patients (see Fig) as well as between siblings; for example, a younger sister, at the age of 15
years, had a moderately enlarged third ventricle and cerebral sulci, but her older sister had only slight cerebral
and cerebellar atrophy by the age of 19 years (not
The identification of the CLN3 gene has provided a
focus for studies attempting to clarify the basic defect
and pathophysiology of the disease. This study is our
first formal attempt to understand the varied symptoms of Batten disease patients with respect to the
1.O2-kb deletion (del), the major mutarion rhar causes
the disease. We found that the extreme variability
in disease severity and MRI findings is partly reflected
in the different genotypes (1.02-kb deU1.02-kb del,
1.O2-kb del/other).
Our subjects, consisting of 27 Batten disease patients
with 1.O2-kb deU1.O2-kb del, showed great clinical
variability between different families and also within
the families. About one-half the patients showed the
typical clinical course with onset of parkinsonian signs
between 12 and 14 years of age and a preceding mental
decline (as described by Sjogren [ 111 in his extensive
genetic analysis). Even during the diagnostic stage, patients with IQs greater than 90, and especially greater
than 100, were few. However, in about one-half the
patients, mental decline took place later than had been
previously described [ 1, 11, 121, beginning in some patients only after 20 years of age. A high I Q at an early
Brief Communication: Jarvela et al: Genotypell’henotype in Batten Disease
stage was not prognostically important, and an early
low I Q did not necessarily indicate rapid mental or
motor deterioration. In one-half the patients, extrapyramidal symptoms appeared late, usually after 18 years
of age. When compared with a previous Finnish series
[ 131 without modern sophisticated rehabilitation and
antioxidant therapy [6], patients belonging to the
present subject group had better-preserved mental abilities and locomotor skills. However, onset of visual
symptoms and epilepsy have remained constant [ 11-
Among the heterozygous patients, there was no difference in the age of onset of visual failure and epilepsy
compared with homozygous patients. However, none
of the heterozygotes showed a rapid clinical course, indicating that the other alleles are associated with a
milder form of Batten disease. Two males from different families have shown an exceptionally benign
course, with no mental deterioration and a high IQ.
Even when compared with the previous patients in the
literature with a protracted course [ 141, these patients
appear to have a less malignant disease. There is a risk
that this phenotype can be overlooked, especially if
vacuolated lymphocytes are not included in the diagnostic battery.
Progression of visual symptoms and epilepsy was
highly concordant, suggesting that it is tightly controlled by the CLN3 gene. However, great variation in
the progression of motor and mental deterioration was
detected among the patients with the 1.02-kb/l.02-kb
deletion. This could be due to environmental effects,
such as the level of training and education, therapeutic
regimens like antioxidants and appropriate anticonvulsive medication, and the influence of other genes outside the CLN3 locus. Noticeable intrafamilial variation
in mental symptoms supports the conclusion that
modifjhg genes may play a role in the pathogenesis of
JNCL. Similar findings have been reported in phenylketonuria [15].
In conclusion, homozygosity for the major 1.02-kb
deletion is always associated with mental and physical
handicap, whereas the heterozygous phenotype can be
extremely benign without affecting the intellectual level
of the patient. Therefore, the diagnostic DNA test has
prognostic value in determining the severity of the disease. Additional prognostic accuracy can be achieved
by brain imaging (MRI) studies, which are useful at
about age 10, to detect the first signal-intensity changes
found in Batten disease.
We thank the Academy of Finland, the Arvo and Lea Ylppo Foundation, the Paediatric Research Foundation (Ulla Hjelt Fund), and
ECA-NCL (BIOMED 2-BMH 4-CT 95-0563) for financial support.
802 Annals of Neurology
Vol 42
No 5
November 1997
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