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GM1 gangliosidosis in adults Clinical and molecular analysis of 16 Japanese patients.

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GMl Ganghosidosis in Adults: Clinical and
Molecular Analysis of 16 Japanese Patients
Kunihiro Yoshida, MD,"? Akihiro Oshima, MD," Hitoshi Sakuraba, MD," Takeshi Nakano, MD,t
Nobuo Yanagisawa, MD,f Koji Inui, MD,S Shintaro Okada, MD,S Ei-ichiro Uyama, MD,W Reiko Namba, MD,'
Kiyohiko Kondo, MD,"" Shin-ichi Iwasaki, MD,W Kiyoshi Takamiya, MD,SS and Yoshiyuki Suzuki, MD*
~~~
-~
~~
Clinical findings were compared with the results of molecular analysis in 16 Japanese patients from 1 0 unrelated
families with the adult/chronic form of GM1 gangliosidosis. Age of onset ranged from 3 to 30 years. Major clinical
manifestations were gait and speech disturbances caused by persistent muscle hypertonia. Dystonic postures and
movements, facial grimacing, and parkinsonian manifestations were commonly seen. Cerebellar signs, myoclonus.
severe intellectual impairment, dysmorphism, or visceromegaly were not observed. A common single-base suhstitution,
5'Ik(ATC)+Thr(ACC). reported in a previous study of ours, was confirmed in 14 patients by the Bst4361 restriction
site analysis; one was a compound heterozygote with another mutation ("57Arg{CGA]+Gln[CXAiZA))
and the others
were homozygotes of this mutation. Clinically, the compound-heterozygous patient showed more severe neurological
manifestations and a more rapid clinical course than those of homozygotes. The homozygotes showed considerable
variations in the age of onset and subsequent clinical course. The 5'lCe+Thmutant allele expressed a significant
amount of P-galactosidase activity, whereas the 457Arg+Gln mutant allele expressed extremely low activity in human
GM1 gangliosidosis fibroblasts. We conclude that these gene mutations causing different residual enzyme activities
are related to the severity of clinical manifestations, but some other genetic or environmental factors contribute to
clinical heterogeneity. The Bsu361 restriction site analysis was performed in 7 families and provided clear results for
the diagnosis of heterozygotes as well as homozygotes of this specific clinical form of GMI gangliosidosis. The technique is applicable to prenatal diagnosis and generic counseling.
Yoshida K, Oshima A, Sakuraba H, Nakano T, Yanagisawa N, Inui K, Okada S, Uyama E-i. Namba R,
Kondo K, Iwasaki S-i, Takamiya K, Suzuki Y . GM1 gangliosidosis in adults: clinical and molecular
analysis of 16 Japanese patients. Ann NeuroI 1902;3 1:328-332
GM 1 gangliosidosis is a hereditary neurovisceral storage disease caused by a deficiency of lysosomal P-galactosidase C 11. Three phenotypes have been identified
on the basis of age of onset and clinical manifestations.
The infantile and late infmtile/ juvenile forms exhibit
severe neurovisceral manifestations with fetal course
in infancy and childhood. Late-onset ("adult" or
"chronic") G M 1 gangliosidosis is an uncommon form
with a more protracted clinical course. This form was
first described in 2 adult siblings by Suzuki and colleagues [ 2 } and several other reports followed C3--8].
The age of onset in this form ranges from 3 to 30 years,
but the main clinical manifestations of basal ganglia
disorders, such as dysarthria, gait disturbance, and dystonia in the neck and extremities, become promirient
in adulthood. Cherry-red spots, dysmorphism, visceromegaly, or severe intellectual impairment have not
been observed. Some patients have been reported to
be only mildly affected and lead normal social lives
after 40 years of age [ S } .
Recently, we identified a specific and common mutation, 5'lIe/ATC)-+Thv1ACC), in S patients with adult1
chronic GM 1 gangliosidosis derived from a central district of Japan "91. This single-base substitution created
a new cleavage site for the restriction endonuciease
Sazll. In this report, we used another enzyme, Bsri361
(which recognizes the same restricrion site as Saul), for
genetic diagnosis of the patients and carriers. The results of molecular analysis were compareci with the
clinical data of the patients.
From the "Dcpartnient of Clinical Genetics, The Tokyo Metropoliran Institutc o f - Medical Science. Tokvo: the +Department of Mrdi-
Received Jun 28, 1991, arid in revised f o r m Aug 1 0 Accepted for
publication Aur 25, 1991.
of Neurology, National Minami Okayama Hospital, Okayama; the
""Department of Neurology, Saku General Hospital, Nagano; the
++Department of Neurology, Saitama Medical School, Saitama; and
the $$Fourth Department of Internal Medicine, Toho Universit:/
School of Medicine, Tokyo, Japan.
328 Copyright 0 1992 by the American Neurological .issociation
Clinii-al Summay of Patients with AdultiChronzc GM 1 Gangliosidosis
Age
(v)
Clinical Features".'
Patient, Ref"
Sex
Consanguinity Onset
Diagnosis Onset Mental
1, TS
2,KT. [ 6 ]
F
F
!
3, HS
hi
F
3-1, AM, IS1
Muscle
Cornea
Bone
CTiMRI BM P-Gal
HIHI-
+(7)
+
-
t
+
-
+
+
AB
N
-
7.0
+
+
-
-
+
AB
NE
5.7
-
-
t
-
7.3
+
-
-
-
-
-
NE
NE
NE
NE
8.5
4.4
5.3
7.0
gab
+
SP
-
+
+
10
17
SP
-
+
+
+
19
18
d s p
-
+
t
+
+
HIHiNI-
+
+
+
N/-
+
+
HINi-
+
-
-
t
t(49)
-
-
+
AB
N
NE
AB
AB
-I-
+(29)
+
+
+
AB
t
7.9
t
-
-
+
N
...
8.9
t
-
-
+
NE
t
-
-
-
AB
t
-
-
-
AB
. ..
+
-
t
.
+(22J
-
+
AB
AB
..
5.0
5.0
ti26)
+
-
AB
t
5.0
45
gd
-
4-3, SM. f 5 I
M
+
30
M
t
8
33
i46
Ra
5 , MF
6, YE
M
M
+
6
33
SP
-
F
8-2, KK
M
9-1, M A
M
9-2. KA
F
10-1, TK, (81 M
10-2, RK, [8] M
10-3, AK, (81 M
-
HO, ['I
Gait
2s
22
30
l,
Pyram
13
<?
+
8-1. YK
Speech ExPyr
+
+
M
4-2, HM, I51
Lboratory"
-
+
gaisp
t
+
+
+
t
12
5P
-
29
ga
-
+
+
2'
SP
-
+
t
3
31
gaisp
t
t
+
Hit
H/NiNIHit
HI -
t
3
28
ga/sp
+
+
t
H/t
-
2'
4
1'
30
SP
-
11'
11-12
14
33
hand
+
SP
~
i
+
t
t
-
t
+
f
+
t
-
+
+
. . 4.2
.
.
.
.
.
5.4
4.7
2.7
"Patients without reference numbers are new cases.
bOnset: initial symptoms (ga = gait disturbance, sp = speech disturbance); mental = mental retardationideterioration; speech = speech
disturbance; ExPyr = extrapyramidal signs (dystonia, rigidity, facial grimacing); Pyram = pyramidal signs (deep tendon reflex/pathological
reflex; H = hyperactive, N = normal); gait = gait disturbance (age that gait became impossible in parentheses; gait possible for others); muscle
= niuscle atrophy or weakness; Cornea = corneal opacity; Bone = flattening of vertebral bodies.
'Signs not observed: cerebellar ataxia, myoclonus, visual impairment, hearing loss, sensory disturbance, cherry-red spots, dysmorphism, or
visceromegaly .
"CTIMRI: neuroimaging studies ( A B = abnormal, N = normal, N E = not examined); BM = form cells in bone marrow; @-Gal =
6-galacrosidase activity (% of normal).
CT
=
computed tomography; MRI = magnetic resonance imaging;
Patients
Clinical data of the 16 patients are summarized in the Table.
There were 4 families with sibling cases: Patients 4-1, 4-2,
4-3,8-1,8-2,9-1, 9-2, 10-1, 10-2, and 10-3. Molecular analysis was performed on 6 patients ( 7 , 9-1, 9-2, 10-1, 10-2, and
10-3) by Nishimoto and associates [IO].
Individual symptoms and signs were relatively homogeneous, but the age of onset was remarkably wide (3-30
years) and the subsequent course was variable. Patient 1, who
showed the most rapid course of progression, could no
longer walk at 9 years of age and became almost vegetative
at 25 years; however, some others were able to walk and lead
almost normal social lives with some difficulty at 45 to 50
years of age. The oldest patient (Patient 6 ) , a Oh-year-old
man, is bedridden and cannot speak at all, but communication
is possible by means of a word panel or a word processor.
In 15 patients, gait disturbance, speech disturbance, o r both,
appeared as initial symptoms and persisted as main symptoms
throughout the course. Only Patient 9-2 complained of difficulty handling with hands at the initial stage of illness. These
symptoms were caused by dystonia with rigidity. Dystonic
postures such as torticollis, facial grimacing, and blepharospasm were commonly observed. Parkinsonian features were
prominent in some patients, such as immobile face, micrographia, bradykinesia, short-stepped gait, and pulsion.
Pyramidal signs were not consistent among patients, and
muscle atrophy or weakness was not common. The latter
were influenced by the duration of the disease and daily activities in some cases and were therefore not easy t o evaluate.
+
= present; - = absent
Cerebellar signs, visceromegaly, dysmorphism, myoclonus,
hearing loss, cherry-red spots, or sensory disturbances were
not observed in any patient. Intellectual impairment was
mild, if present.
Corneal opacity was detected in 3 patients, but visual acuity was not disturbed. Flattening of the vertebral bodies was
found radiologically in 12 patients. Kyphoscoliosis was frequently seen, probably because of bone deformity and persistent dystonia. Patients were generally slender and short in
height. Very mildly affected patients had only slight speech
or gait disturbance caused by dystonia with rigidity and lived
almost normal social lives after 40 years of age; Patient 4-2
was a schoolteacher and Patient 4-3 was a self-defence force
officer.
Routine hematological and cerebrospinal fluid examinations were negative. Foam cells were found in the bone marrow of 2 of 4 patients examined (Patients 7 and 10-3). Other
laboratory tests, including electrocardiograms, electroencephalograms, and electromyograms, showed no remarkable
changes. Computed tomography (CT) scans revealed dilation
of the anterior horns of the lateral ventricles and cortical
atrophy in the cerebrum in 11 of 14 patients examined.
Proton-dense and T2 weighted magnetic resonance imaging
(MRI) showed high intensity in the putamen bilaterally in 3
patients [7,81.
Some patients had been followed under the clinical diagnosis of cerebral palsy, torsion dystonia, parkinsonism, or striatonigral degeneration before the final diagnosis was established biochemically. P-galactosidase activity, assayed by the
Yoshida et al: AdultiChronic GM1 Gangliosidosis
329
(bp)
C
1
2
3
4-1
5
6
7
8-1 8-2 9-1 9-2 10-1 10-2 10-3
170-
92
7a
Normal
1
Mutant
I
I
170 bp
78bp
I
92bp
I
t
1
Bsu 36 I (CC TNAGG)
Fig I , Restriition site arzalysis of genomic D N A f r o m 14 putients. A 170-bp fragment was amplified b.y pohmerae chain
reaction (PCR). digested with Bsuibl, dectropboreJed in 4%
agurose gel. and stuined u i t h ethidium bromide. The I m e number corvesponrh to the patient number. The ''Ile+Thr mutant
a1Me u m dipeJted LO produce 9 2 - b ~aild 78-bp fizgmmts. The
PCR product from Patient I ((am 1 i u'a.cpartially digested
and all the olberJ u'ere tnnzpletely digested. Lane t7 = normal
control.
Results
Digestion of the 170-bp fragment with B.11~361produced 78-bp and 92-bp fragments in 1-3 patients from
9 families (2, 3, 4-1, 5 , 6, 7, 8-1, 8-2, 9-1, 9-2,
10-1, 10-2, and 10-3), indicating their homozygosity
for 5'Ilr-tThr mutation (Fig I ) . Among them, 2 (Patients 2 and 3) had been confirmed to have this mutation also by sequence analysis [ 9 } . An undigested 170bp fragment was detected in addition to the digested
78-bp and 92-bp fragments in 1 patient (Patient I ) , and
method reported by Sakuraba and associates 111, showed
the
diagnosis of a heterozygote of this mutation 'was
low but significant amounts of the residual enzyme activity
established;
another single-base substitution i ',4rg
(4-109; of the control mean) in this form of G M l ganglio{CGA+Gln{CAA}),
as well as the common mutation
sidosis and was inversely related to the severity of the clinical
already
described,
had
been founcl by sequence analymanifesrations.
sis in a previous study [91. Molec-ular analysis was riot
performed o n the siblings of Patient 4-1 (Patients 4-2
Materials and Methods
and 4-3).
hldecdar Genetic Analysis
W e applied the Bszr361 restriction site analysis for
Heparinized peripheral blood samples ( 10-20 mi) were obheterozygote detection in 7 Families. T h e 170-bp fragtained from patients and their family members. The details
ments were only partially digested with B.1~361
in the
of molecular analysis procedures have been reported elseparents of Patients 2, 3, 7, 8-1, and 8-2, and in younger
where [9,12). Genomic DNA was prepared according to
brothers of Patients 2 and 3 (Fig 2 ) . T h e parents of
the standard method and used as a template for polymerase
other
families ( 4 , 9? and 10) and a healthy sibling of
chain reaction (I'CR) amplification of a l7O-bp D N A (cDNA
4-1 showed the same results (data not shown).
Patient
#110-279 {13]1. The oligonucleotide primers were as folT
h
e
mother
of Patients 9-1 and 0-2 was deceaseti and
l o w ~ : 5'-AATGCCACCCAGAGGATGTlTGfiAA'IT-3'
was
not
examined
in this study. T h e ciiagnosis oi the
(sense) and 5'-GTCTGGATGGCGTTCAGCCCAGCCA"lIe-+Thr mutant heterozygote was thus confirmed in
TC-3' (antisense). The PCR reaction mixture (100 pL) contained 50 mM potassium chloride, 10 mM Tris hydrochloride
all parents and siblings examined.
(pH 8.3), 1.5 mM magnesium chloride, O.Ol(% (wiv)gelatin,
1 pg each of sense and antisense primers, 0.1 mP4 each of
2'-deoxynucleoside 5'-triphosphates, and 5 U T u y D N A
polymerase (Perkin Elmer-Cetus, Norwalk, NJ). Ta prevent
evaporation, the mixture was overlaid with 100 pL (if mineral
oil, and the reaction was amplified 30 cycles by denaturation
at 94°C for 1 minute, annealing at 65°C for 2 minutes, and
extension at 72°C for 1 minute. This 170-bp product was
digested with Bsu.361 (New England BioLabs, Beverly, MA),
electrophoresed in 4q agarose gel, and stained wirh ethidium bromide.
330 Annals of Neurology
Vol 31
No 3 March 1992
Discussion
In this study, clinical manifestations were fcxind t o be
homogeneous in the Japanese patients with the aclult-/
chronic form of G M 1 gangliosidosis. T h e initial symptoms of this clinical form were almost always gait &turbance, speech disturbance, o r both, which were
most prominent during the course of the disease and
resulted mainly from dystonia with rigidity. Dystonic
postures and movements of extremities, trunk, and
-170
-9278
Fig 2. Restriction site analysis of the family members of patients. Analytical procedures are as described in F i g l . The
pohmerase chain reaction products from the parents and younger
brothers toere digested with Bsu.361. D = D N A markers
Id x 174 phage DNAIHaeIlI digest); C = normal control:
F = father: M = mother: B = brother: I = Family 2: I I =
Family 3; I I I = Famih 7 ; IV = Family 8.
neck; facial grimacing; or blepharospasm were common manifestations. Parkinsonian features, such as immobile face, bradykinesia, or short-stepped gait, were
observed in some cases.
These clinical signs of basal ganglia disorders were
supported by CT and MRI, which demonstrated abnormalities in the caudate nucleus and putamen in
most patients examined. Postmortem examinations in
two autopsy studies [ 14- 17) revealed that intraneuronal storage of ganglioside G M 1 localized predominantly to the basal ganglia and other areas of the central
nervous system appeared relatively unaffected. These
pathological findings were consistent with clinical manifestations described herein.
Neurological or somatic abnormalities commonly
seen in the infantile and late infantilei juvenile forms,
such as mental retardation/deterioration, dysmorphism, visceromegaly, or cherry-red spots, were not
observed in this clinical form. Cerebellar signs, myoclonus, or generalized bone dysplasias characteristic of
other forms of P-galactosidase deficiency (galactosialidosis or Morquio Syndrome type B) were not observed. These positive or negative clinical signs and
symptoms are completely in accord with those described in the patients reported from the United States
c3, 41.
In GM2 gangliosidosis, another gangliosidosis
caused by lysosomal hexosaminidase deficiency, patients with late onset disease had a higher residual enzyme activity ClS, 191, and the central nervous system
lesions in late-onset forms are predominantly distributed in subcortical gray matter (cerebellar granular
cells, hippocampus, brainstem nuclei, and spinal cord)
[20,2 11. This selective glycolipid accumulation in the
brain is characteristic of the late-onset form of gangliosidosis, whereas the early-onset form shows ubiquitous
neuronal storage. This finding probably reflects the different rates of influx and turnover of the substrate in
various areas and cell types of the central nervous
system.
Despite symptomatic homology, a marked variation
was observed in the age of onset and clinical course,
and we looked for the genetic basis causing the heterogeneity of this clinical form. After cloning cDNA for
human P-galactosidase [ 131, we established an analytical system for identification of mutations in GM1 gangliosidosis. In a previous study C93, we used the restriction enzyme Saw1 for analysis of the common mutation
site described herein in patients with adultlchronic
GM 1 gangliosidosis; however, another restriction enzyme, Bru361, was tried for restriction site analysis in
this study only because it was less expensive and more
commercially available. These two enzymes recognize
the same seven-nucleotide sequence and are therefore
mutually interchangeable. In fact, digestion of the
PCR-amplified 170-bp fragment with Bsu36I produced
the same digestion fragments as those produced after
digestion with SuuI in the previous study [91.
All 14 patients examined by restriction site analysis
in this study were found to have a common single-base
substitution: S'Ile(ATC)*Thr/ACC) (mutation A [91).
Thirteen were homozygotes and 1 was a compound
heterozygote associated with another mutation, 457Arg
(CGA)-+Gln(CAA)(mutation C [91). It has been concluded that patients with adult/chronic G M 1 gangliosidosis of Japanese origin are genetically homogeneous
in contrast to remarkably heterogeneous gene mutations in infantile patients (Yoshida et al. Unpublished
data) {9}. The pathogenesis of the heterogeneous phenotypic expression in these genotypically homogeneous adults with GM1 gangliosidosis is currently unYoshida et al: AdultiChronic GM1 Gangliosidosis 331
mown. We may have to search for some other genetic
)r environmental factors.
In a transient expression study in cultured fibroblasts
tom a patient with infantile GM 1 gangliosidosis, the
nutant A allele expressed a higher P-galactosidase acivity than the mutant allele C, which showed an almost
:omplete loss of activity [U]. Clinically, the compound
ietcrozygote AIC (Patient 1) showed more severe
neurological manifestations and more rapid clinical deterioration than the homozygotes A/A (other patients).
There were some variations in the severity and course
of the disease among the homozygotes, however, even
in the same family; severe neurological manifesc.ations
developed in Patients 4-1, 10-2, and 10-3 earlier than
in Patients 4-2, 4-3, and 10-1, respectively. These findings suggest that the phenotypic expression is modified
also by other genetic or environmental factors in inherited diseases like adult/chronic GM 1 gangliosidosis, although it is mainly determined by a specific single gene
mutation.
The Bsu361 restriction site analysis was performed
in some parents and siblings of the patients in this
study for carrier diagnosis of the mutant A allele, and
the tentative diagnosis suggested by enzyme arjsays
was clearly confirmed in all subjects. It is well known
that the enzyme diagnosis for heterozygous carriers is
not always reliable because there is an overlap between obligate heterozygotes and normal homozygotes
caused by individual variations and technical factors
inherent in the assay procedure itself 122). It is therefore desirable, if possible, to establish a more reliable
method for detection of heterozygous carriers. W e
conclude that the diagnostic method in this study using
restriction site analysis will serve as a useful and convenient laboratory test for carrier and prenatal diagnoses
of aduh'chronic GM 1 gangliosidosis in the future.
This work was supported by grants from the Ministry of Education,
Science and Culture, and from the Ministry of Health and Welfare
of Japan.
The aurhors wish to thank D r Asayo Ishizaki (Merropolitan hledical
Center o f the Severely Handicapped, Tokyo, Japan), D r Shin-ichi
Nakagawa (Saku General Hospital, Nagano, Japan), and Ilrs Masao
Ushiyama and Norinao Hanyu (Nagano Red Cross Hospiml, Nagano, lapan) for supplying blood samples, skin fibroblasts, or hoth,
from the patients The excellent technical assistance of Ms Haruko
Nakashima and Ms Keiko lshii is appreciated.
References
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MM, Suzuki K, eds. Ganglioside structure, function. and biomedical potential. N e w York: Plenum, 1984:4 19-42!,
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leukocytes. J Peciiatr 197 I ;;'8.64 1-64'
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