Type 3 GM 1 gangliosidosis: characteristic MRI findings correlated with dystonia U
Uyama E, Terasaki T, Watanabe S, Naito M, Owada M, Araki S, Ando M. Type 3 G M l gangliosidosis: characteristic MRI findings correlated with dystonia. Acta Neurol Scand 1992: 86: 609-615. 0 Munksgaard 1992.
’,
E. Uyama’, T. Terasaki S. Watanabe M. Naito2, M.Owada3, S. Araki’, M. Ando’
’,
’ First Department of Internal Medicine,
* Second Department of Pathology, Kumamoto University School of Medicine, Department
We describe three brothers with type 3 GM1 gangliosidosis presenting as of Pediatrics, Nihon University School of dystonia. The ages of the patients when examined were 28, 31, and 33. They Medicine, Tokyo, Japan had developed dysarthria with facial grimacing since early childhood. The common neurological sign was generalized dystonia. Both dystonic postures and dystonic movements resulting from varying degrees of fixed rigidity of each muscle involved did not disappear when the patients were lying or sitting Key words: type 3 G M I gangliosidosis; symptomatic dystonia; MRI; selective putarninal relaxed. There was no correlation between the severity of dystonia and lesions the residual activities of acid pgalactosidase. Magnetic resonance imaging (MRI) showed bilaterally symmetric high intensity lesions only in the putamen E. Uyama, First Department of Internal Medicine, Kumamoto University School of on TZweighted and proton density images. Selective putaminal changes Medicine, Honjo 1-1- 1, Kumamoto, 860 Japan. on MRI may be the lesions most responsible for symptomatic dystonia in this disorder. I Accepted for publication June 22, 1 9 9 2
GM 1 gangliosidosis is a rare neurovisceral storage disease caused by an inherited deficiency of acid bgalactosidase resulting from mutations in this gene (1,5,6). Three phenotypes have been recognized on the basis of the onset and clinical manifestations. Type 1 (infantile) is a fatal form associated with severe neurovisceral involvement before two years of age (1). Type 2 (late infantile or juvenile) patients reveal less severe manifestations and death occurs later, usually between ages 3 and 10 (1). Patients with type 3 (adult or chronic) have prolonged survival, mild bony abnormalities, and neurological signs including dystonia, choreoathetotic movements, dysarthria, and pyramidal signs (1-14). Several single base mutations within the human bgalactosidase gene have been identified in subtypes (15, 16). We have recently found three brothers with type 3 GM1 gangliosidosis presenting as dystonia. To clarify the pathogenesis of dystonia in this disorder, brain magnetic resonance imaging (MRI) was performed in addition to clinical analysis. Case reports and methods
The pedigree of the affected Japanese family is shown in Fig. 1. Each patient was the child of first cousins.
- A 28-year-old man, was the proband of the family. He was born after a normal pregnancy and delivery. His early development progressed nor-
Patient I.
mally until age 3, when his parents noticed difficulties in stammering and gait disturbance. These neurological abnormalities progressed slowly, and facial grimacing with dystonic postures in the limbs appeared 7 years later. At 22 years of age, he could not walk at all. On admission, he was bedridden in a state of dysphonia phonatorica, subluxation of the mandible, marked scoliosis, and joint contracture at the ankle secondary to severe dystonia. Communication was possible only by pointing to written words. He showed facial grimacing, torticollis, and marked dystonic postures and movements of the trunk and limbs. Both neck and limbs were stiff, and jaw jerk reflex was hyperactive. Other tendon stretch reflexes were normal, and a Chaddock sign was elicited on the left. Laboratory studies revealed a leukocyte count of 3600/mm3, a hemoglobin of 10.3 g/dl, and a hematocrit of 30.8%. The level of serum ceruloplasmin and copper were normal. In the cerebrospinal fluid (CSF), homovanillic acid (HVA) was 12.4 ng/dl (normal, 41.8-44.8), and 5-hydroxyindole-acetic acid was 22.1 ng/ml (normal, 11.2-29.2). Nerve conduction velocities and electroencephalogram (EEG) were normal. Needle electromyography (EMG) showed normal muscular units but surface EMG disclosed continuous, tonic, and non-reciprocal discharges in agonist and antagonist muscles. Radiographic studies of bones demonstrated flattening of the vertebral bodies with irregular intervertebral 609
Uyama et al. I
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111
k ''Ic* X '9&
0
IV IV
33y Patient 3
31y
Patient 2
I8y
Patient 1
a: a: 0 0: t
: Normal : Helerorygoles Affected
Helerorygoles
:Dead
Fig. 1. The pedigree of the family. Arrow indicates the proband of this family.
spaces. Cranial computed tomographic (CT) scan showed diffuse cerebral atrophy with dilated frontal horns of the lateral ventricles. Single photon emission computer assisted tomography using 123-iodinediethylene triamine pentaacetic acid revealed no significant perfusion defect. Patient 2. - was the 31-year-old elder brother of Patient 1. His early development was normal until age 3, when his parents noticed stammering and gait disturbance. Motor control deteriorated slowly but progressively, and he was unable to speak at age 7. Therefore, he could not complete elementary school. By age 22, he was totally confined to a wheelchair. Examination disclosed coarseness of the face, slight corneal opacities, and joint limitations. Intelligence was deteriorated, and his speech was limited to simple words. Facial grimacing with dystonia in the neck and limbs was easily elicited by emotional stress. Neither dystonic postures or movements resulting from varying degrees of fixed rigidity of each muscle involved did not disappear when the patient was lying or sitting relaxed. Tendon reflexes were slightly increased, but the Babinski sign was not observed. Routine laboratory studies were unremarkable except for mild leukopenia. X-ray examination of the vertebral bodies showed moderate platy spondylia. Patient 3. - the 33-year-old elder brother of Patients 1 and 2, was the product of a normal full-term pregnancy and delivery. He had normal psychological development until age 11, when walking abnormalities and speech difficulties became evident. At age 20, he developed intellectual impairment. Eleven years later, he underwent total hip replacement arthroplasty for osteoarthritis of the right hip with necrotic changes of the femoral head. On examination, he measured 1.65 m in height and weighed 54 kg. 610
Facial appearance was normal. The liver and spleen could not be felt. He was alert and intelligence was only mildly deteriorated. He could not move the tongue rapidly or speak fluently. There was no limb weakness or muscle atrophy. Muscle stretch reflexes were slightly increased. Facial grimacing and dystonia of the limbs were observed but they were milder than in Patients 1 and 2. Routine blood analysis and EEG were normal. Radiological studies of bones demonstrated moderate platyspondylia, especially at the lumbar level. CT scan disclosed moderate brain atrophy with widening of the frontal horns of the lateral ventricles. Enzyme assays - The procedures for enzyme assays were essentially the same as described previously (17, 18). The activity of p-galactosidase was determined by using 4-methylumbelliferyl (MU)+ galactoside as substrate. The activity of neuraminidase was measured with 4-MU-a-D-N-acetylneuraminic acid as substrate. The other lysosomal hydrolases were also assayed with 4-MU as substrates. The protein content of the enzyme sources was determined by the method of Lowry and coworkers (19). Ultrastructuralstudies - For electron microscopy, the major part of the bone marrow aspirate and rectal mucosa from Patient 1 were immediately fixed in 2.5% glutaraldehyde, and postfixed in 2% osmium tetroxide. The tissues were embedded in Epon 812 and sectioned as described previously (18). Magnetic resonance imaging - MRI scans were performed with a spin echo sequence on a 0.22-Tesla Signa unit for Patient 1 and on a 0.5-Tesla Signa unit for Patient 2. T1-weighted (TR = 500 msec; TE = 40 msec), proton density (TR = 2000 msec; TE = 40 msec), and T2-weighted (TR = 2000 msec; TE=80msec) images were obtained in the axial and coronal planes. In Patient 3, we did not perform MRI because of metal implantation in his right hip. Results
Enzyme activities - Acid 4-MU-pgalactosidase activities in cultured skin fibroblasts of Patient 1 and in the lymphocytes of Patients 1, 2, and 3 were decreased to about 5 % of the normal control (Fig. 2). The same activities in the parents were 50% to 70% of the control values. The activities of 4-MU-aneuraminidase in the lymphocytes of Patient 1 were normal; the activities of 4-MU-phexosaminidase A & B in cultured skin fibroblasts of Patient 1 and in the lymphocytes of all patients were also normal.
MRI findings in Type 3 GM1 gangliosidosis Drug therapyfor dystonia - Trials of diazepam up to a dose of 20 mg/day and L-DOPA up to 1 g/day for Patient 1 slightly improved the dystonia, but trihexyphenidyl up to 14 mg/day was not effective. Discussion
Fig. 2. pH activity curves of pgalactosidase in tissues from control, Patients 1, 2, and 3, and parents. Activities were measured with 4-methylumbelliferyl (MU)-pgalactoside as substrate. Values of 4-MU-pgalactosidase are expressed as nmol/mg protein/ hr.
Electron microscopy - Three kinds of intracytoplasmic membrane-limited inclusions were observed in macrophages. In the bone marrow, spindle- or irregular-shaped tubular structures composed of fine fibrils, about 50 nm in width were accumulated in several macrophages (Fig. 3a). In the rectal mucosa, most of the macrophages possessed a large number of clear vacuoles, about 1-2 pM in diameter, showing the appearance of foam cells (Fig. 3b). In a few macrophages in the rectal mucosa, round osmiophilic multilamellar concentric inclusions ranging 500 to 2000 nm in diameter were occasionally found (Fig. 3c). MRZfindings - The T1-weighted MRI showed diffuse brain atrophy, predominantly of the caudate nucleus and putamen in Patients 1 and 2. The ratio of the maximum bilateral ventricular diameter, FH/CC (20), was 1.68 in Patient 1 and 1.86 in Patient 2 (normal; 1.8-3.7). That of Patient 3 by X-ray CT was 2.23. The T2-weighted MRI demonstrated bilaterally symmetrical high intensity lesions only in the putamen in both Patients 1 and 2 (Figs. 4a, 4c). Such abnormalities were less evident but still observed on proton density images (Figs. 4b, 4d). Putaminal lesions could not be detected on T1weighted images.
We diagnosed GM 1 gangliosidosis based on the following data. Acid 4-MU-pgalactosidase activities in cultured skin fibroblasts of Patient 1 and in the lymphocytes of all three patients were reduced to about 5 % of the normal control value. The activities of 4-MU-pgalactosidase in the parents were 50% to 70% of normal value. The activities of other lysosomal enzymes including a-neuraminidase, were normal in lymphocytes of Patient 1. In addition, electron microscopic examinations disclosed membranelimited intracytoplasmic inclusions of lysosomal origin in macrophages obtained from the bone marrow and rectal mucosa as seen in cases previously reported ( 5 , 8). Furthermore, a specific and common mutation of the human pgalactosidase gene, 5 lZle(ATG)+ Thr(ACG), in Japanese patients with type 3 GM1 gangliosidosis had been identified in our patients (16). In this family, the most prominent and common neurological sign was generalized dystonia. In contrast to idiopathic dystonia (21,22), both dystonic postures and the movements resulting from varying degrees of fixed rigidity of each muscle involved failed to disappear when the patients were lying or sitting relaxed. This is characteristic of symptomatic dystonia (23). We also observed some degree of correlation between the severity of dystonia and that of brain atrophy among our patients. However, we found no correlation between the severity of dystonia and the residual activities of acid 4-MU-Pgalactosidase. To date, more than 20 patients with type 3 GM1 gangliosidosis have been reported in the literature (Table 1). Although the age of onset and the subsequent course were variable, dysarthria, which should result from dystonia, was commonly seen among them (2- 12). Subsequently, extrapyramidal signs such as limbs’ dystonia, choreoathetotic movements, plastic rigidity, or facial grimacing were frequently observed except in a few atypical cases (10). Neuropathologic study of type 3 GM1 gangliosidosis was performed in two cases, revealing that the intraneuronal storage of cytoplasmic membranous material was localized primarily in the neurons of basal ganglia including the caudate nucleus, putamen and globus pallidus (5, 6). This selective intraneuronal storage pattern, had been confirmed biochemically (13, 14). However, our neuroradiological study using MRI showed only putaminal lesions on T2-weighted and proton density images. Interest61 1
Uyama et al.
Fig. 3. Electron micrographs of macrophages obtained from Patient l . Three kinds of intracytoplasmic inclusions. (a) Tubular or fibrillar structures in bone marrow macrophage ( x 30000).
(b) Electron-lucent vacuoles in a macrophage of the rectal mucosa ( x 16000). (c) Concentric multilamelar structures in a macrophage of the rectal mucosa ( x 20000).
612
MRI findings in Type 3 GM1 gangliosidosis
Fig. 4. Magnetic resonance scan of Patient 1 (a, b) and Patient 2 (c, d). (a, c) Axial T2-weighted images show bilaterally symmetrical high intensity lesions only in the putamen. (b, d) These characteristic findings are less evident but still observed on coronal proton density images.
ingly, this pattern of MRI was quite similar to the Japanese case reported by Inui and colleagues (12). The reason for selective putaminal lesions on MRI remains obscure, but we presume that the accumulation of GM1 ganglioside may be most prominent in the putamen which is well-known as the largest nucleus in the basal ganglia. Thus this pattern of MRI indicates that the putaminal changes may be the lesions most responsible for symptomatic dystonia in type 3 GM1 gangliosidosis. With the increasing availability of MRI, more reports of MRI findings in cases of metabolic diseases involving basal ganglia are being done. In Wilson
disease, bilaterally symmetrical areas of abnormal signal were seen in the lenticular, thalamic, caudate, and dentate nuclei, as well as in the brainstem (2426). Besides, a pattern of symmetrical hyperintense lesions on T2-weighted images involving the basal ganglia and brainstem, with predominant involvement of the putamen, is highly specific for subacute necrotizing encephalomyelopathy (Leigh syndrome) (27). In comparison with the MRI findings of our cases, the lesions should be frequently detected on T1-weighted images as low intensity lesions not localized in the putamen. MRI is also useful in the diagnosis of Hallervorden-Spatz syndrome, which is 613
Uyama et al. Table 1. Clinical features of type 3 GM, gangliosidosis
Author
Age
Sex
Suzuki (1977)
34y
F M M M M M F M M F M M F F F M F F F M M M M
30y Stevenson (19781
Wenger ( 1980) Goldman ( 198 1) Ohta (1983) Nakano (1985)
Ushiyama (1985) Mutoh (1986)
Guazzi (1988)
lnui ( 1990) Present cases
19y 27y 41y 19y 25y 27y 51y 38y 45y 43y 22y 54y 43y 27y 27y 24y 17y
32y 28y 31y 33y
Onset
Corneal opacity
Platyspondylia dysplastic dysplastic
t n.d.
t t t n.d.
t t
t
n.d. n.d. n.d.
t t t
t
Intellectual impairment
t t t (la461 t t (iQ43) t t t (1066)
t (1081) t (1063) t (1060) t (la601 t (IQ70) t t (1060) t (la81I t t t
Dysarthria
t t
t t t t t t
t t t t
t t t t t t t
t t t
t
Involuntary movement
Pyramidal sign
bs., gri. bs., gri. athetoid choreic athetoid dtstonia dystonia dystonia
t t t t t
dystonia dystonia dystonia dystonia myoclonus tremor myoclonus athetoid athetoid athetoid dystonia dystonia dystonia dystonia
t
References
t t t
-
t t
(91 (10)
t t t t t
(111
-
(12)
t t
t
n.d.: not done, b.s.: blephalospasm, gri.: grimacing
known as “eye-of-the-tiger” sign in the globus pallidus (28), and in GM2 gangliosidoses, which appears as symmetrical hypointense thalami on T2weighted images (29). Increased signal in the putamen on TZweighted images is also shown in patients with post-infarct dystonia, post-infectious dystonia, glutaric aciduria, and unclassified secondary dystonia (30). Thus, the pattern of MRI in our patients is not specific but characteristic for type 3 GM 1 gangliosidosis. In conclusion, MRI is clearly useful for assessing the involvement of basal ganglia in patients with type 3 GM 1 gangliosidosis. Selective putaminal changes on MRI may be the lesions most responsible for symptomatic dystonia characteristic of this disorder. Acknowledgements We thank Dr. Sadaaki Okamoto of the Department of Neurology, Musashigaoka Hospital, Kumamoto, and Dr. Kohei Ise of the Department of Orthopedics, Kumamoto Municipal Hospital, for providing the patients. We also wish to thank our colleague Dr. Mineharu Sugimoto, and Dr. Teruo Kitagawa of the Department of Pediatrics, Nihon University School of Medicine, Tokyo, for helpful advice.
References 1. O’BRIENJS. PGalactosidase deficiency (GM 1 gangliosidosis, galactosialidosis, and Morquio syndrome type B); ganglioside sialidase deficiency (mucolipidosis IV). In: SCRIVER CR et al., eds. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill, 1989: 1797-1806.
614
2. SUZUKI,Y, NAKAMURA N, FUKUOKAK, SHIMADA Y, UONOM. PGalactosidase deficiency in juvenile and adult patients: report of six Japanese cases and review of literature. Hum Genet 1977: 36: 219-229. 3. STEVENSON RE, TAYLORHA, PARKSSE. Pgalactosidase deficiency: prolonged survival in three patients following early central nervous system deterioration. Clin Genet 1978: 13: 305-313. 4. WENGERDA, SATTLERM, MUELLER OT, MYERSGG, SCHNEIMAN RS, NIXONGW. Adult GM1 gangliosidosis: clinical and biochemical studies on two patients and comparison to other patients called variant or adult GM1 gangliosidosis. Clin Genet 1980: 17: 323-334. 5. GOLDMAN JE, KATZD, RAPINI, PURPURADP, SUZUKI, K. Chronic GM1 gangliosidosis presenting as dystonia: I. Clinical and pathological features. Ann Neurol 1981: 9: 465475. 6. KONDOK, OGUCHIK, YANAGISAWA N, MITSUIZ, ISHII Z. Chronic GM1-gangliosidosis: an adult case of localized neuronal storage in the basal ganglia. In: Abstracts of the 9th International Conmess of NeuroDatholom. Vienna. 1982: 221. 7 / . OHTAK, TSUJI-S, MIZUNO Y , ATGMI T, YAHAGIT, MIYATAKE T. Type 3 (adult) GM1 gangliosidosis: case report. Neurology 1985: 35: 1490-1494. 8. NAKANOT, IKEDA S, KONDOK, YANAGISAWA N, TSUJI S. Adult GM1-gangliosidosis: clinical patterns and rectal biopsy. Neurology 1985: 35: 875-880. 9. USHIYAMA M, IKEDA S, NAKAYAMA J, YANAGISAWA N, HANYU N, KATSUYAMA T. Type I11 (chronic) GM1gangliosidosis: histochemical and ultrastructural studies of rectal biopsy. J Neurol Sci 1985: 71: 209-223. 10. MUTOHT, SOBUEI, NAOIM, MATSUOKA Y, KIUCHIK, SUGIMURA K. A family with Pgalactosidase deficiency: three adults with atypical clinical patterns. Neurology 1986: 36: 54-59. 11. GUAZZIGC, D’AMOREI, VAN HOOF F et al. Type 3 (chronic) GM, gangliosidosis presenting as infanto-choreo-
MRI findings in Type 3 GM1 gangliosidosis athetotic dementia, without epilepsy, in three sisters. Neurology 1988: 38: 1124-1127. 12. INUI K, NAMBAR, IHARAY et al. A case of chronic GM1 gangliosidosis presenting as dystonia: clinical and biochemical studies. J Neurol 1990: 237: 491-493. T, SUZUKI K. Chronic GMl gangliosidosis pre13. KOBAYASHI senting as dystonia: 11. Biochemical studies. Ann Neurol 1981: 9: 476-483. 14. TAKETOMI T, HARAA, KASAMAT. Cerebral and visceral
organ gangliosides and related glycolipids in G M l gangliosidosis type 1, type 2 and chronic type. In: LEDEEN RW et al., eds. Adv Exp Biol, vol. 174: Ganglioside structure, function, and biomedical potential. New York: Plenum Pub CO., 1984: 419-429. 15. YOSHIDAK, OSHIMAA, SIMMOTOM etal. Human bgalactosidase gene mutations in GM1-gangliosidosis: a common mutation among Japanese adult/chronic cases. Am J Hum Genet 1991: 49: 435-442. 16. NISHIMOTO J, NANBAE, INUIK, OKADAS, SUZUKIK. G M 1-gangliosidosis (genetic Pgalactosidase deficiency): identification of four mutations in different clinical phenotypes among Japanese patients. Am J Hum Genet 1991: 49: 566-574.
17. OWADA M, SAKIYAMA T, KITAGAWA T. Neuropathic Gaucher’s disease with normal 4-methylumbelliferyl-Bglucosidase activity in the liver. Pediatr Res 1977: 11: 641-646. 18. UYAMA E, TAKAHASHI K, OWADA M et al. Hydrocephalus, corneal opacities, deafness, valvular heart disease, deformed toes and leptomeningeal fibrous thickening in adult siblings: a new syndrome associated with Pglucocerebrosidase deficiency and a mosaic population of storage cells. Acta Neurol Scand (in press). 19. LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with Folin phenol reagent. J Biol Chem 1951: 193: 265-275. 20. BARRAN, HEINZEWJ, DOBBENGD, VALVASSORI GE,
SUGAR0. Bicaudate index in computerized tomography of
H. Uber eine eigenartige Kramptkrankheit des 21. OPPENHEIM kindlichen und jugendlichen Alters (Dysbasia lordotica progressiva, Dystonia musculorum deformans). Neurol Centralbl 1911: 30: 1090-1107. 22. YANAGISAWA N, GOTOA. Dystonia Musculorum Deformans: analysis with electromyography. J Neurol Sci 1971: 13: 39-65. 23. KANAZAWA I. Clinical pathophysiology of basal ganglia dis-
ease. In: VINKENPJ et al., eds. Handbook of clinical neurology, vol. 49: Extrapyramidal disorders. Amsterdam: Elsevier Sci Pub, 1986: 65-85. JM, STEINERRE, JENKINS WJ, 24. LAWLERGA, PENNOCK SHERLOCK S, YOUNGIR. Nuclear magnetic resonance (NMR) imaging in Wilson disease. J Comput Assist Tomogr 1983: 7: 1-8. 25. AISENAM, MARTELW, GABRIELSEN TO, GLAZERGM,
BREWERG, YOUNGAB, HILL G. Wilson disease of the brain: MR imaging. Radiology 1985: 157: 137-141. S, YOUNGAB, KLUINK etal. 26. STAROSTA-RUBINSTEIN Clinical assessment of 3 1 patients with Wilson’s disease: correlations with structural changes on magnetic resonance imaging. Arch Neurology 1987: 44: 365-370. 27. MEDINAL, CHITL, DEVIVODC, HILALSK. MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect. AJNR 1990: 11: 379-384. 28. SETHI KD, ADAMS RJ, LORINGDW, GAMMALT.
Hallervorden-Spatz syndrome: clinical and magnetic resonance imaging correlations. Ann Neurol 1988: 24: 692694. J, BRISMER G, COATESR, GASCON G, OZAND 29. BRISMAR
P. Increased density of the thalamus on CT scans in patients with GM2 gangliosidoses. AJNR 1990: 11: 125-130. JN, HILALSK, SILVERAJ, DEFENDINIR, 30. RUTLEDGE FAHNS. Magnetic resonance imaging of dystonic states. In: FAHN S et al., eds. Advances in neurology, vol. 50: Dystonia 2. New York: Raven Press, 1988: 265-275.
Huntington disease and cerebral atrophy. Neurology 1978: 28: 1196-1200.
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Uyama E, Terasaki T, Watanabe S, Naito M, Owada M, Araki S, Ando M. Type 3 G M l gangliosidosis: characteristic MRI findings correlated with dystonia. Acta Neurol Scand 1992: 86: 609-615. 0 Munksgaard 1992.
’,
E. Uyama’, T. Terasaki S. Watanabe M. Naito2, M.Owada3, S. Araki’, M. Ando’
’,
’ First Department of Internal Medicine,
* Second Department of Pathology, Kumamoto University School of Medicine, Department
We describe three brothers with type 3 GM1 gangliosidosis presenting as of Pediatrics, Nihon University School of dystonia. The ages of the patients when examined were 28, 31, and 33. They Medicine, Tokyo, Japan had developed dysarthria with facial grimacing since early childhood. The common neurological sign was generalized dystonia. Both dystonic postures and dystonic movements resulting from varying degrees of fixed rigidity of each muscle involved did not disappear when the patients were lying or sitting Key words: type 3 G M I gangliosidosis; symptomatic dystonia; MRI; selective putarninal relaxed. There was no correlation between the severity of dystonia and lesions the residual activities of acid pgalactosidase. Magnetic resonance imaging (MRI) showed bilaterally symmetric high intensity lesions only in the putamen E. Uyama, First Department of Internal Medicine, Kumamoto University School of on TZweighted and proton density images. Selective putaminal changes Medicine, Honjo 1-1- 1, Kumamoto, 860 Japan. on MRI may be the lesions most responsible for symptomatic dystonia in this disorder. I Accepted for publication June 22, 1 9 9 2
GM 1 gangliosidosis is a rare neurovisceral storage disease caused by an inherited deficiency of acid bgalactosidase resulting from mutations in this gene (1,5,6). Three phenotypes have been recognized on the basis of the onset and clinical manifestations. Type 1 (infantile) is a fatal form associated with severe neurovisceral involvement before two years of age (1). Type 2 (late infantile or juvenile) patients reveal less severe manifestations and death occurs later, usually between ages 3 and 10 (1). Patients with type 3 (adult or chronic) have prolonged survival, mild bony abnormalities, and neurological signs including dystonia, choreoathetotic movements, dysarthria, and pyramidal signs (1-14). Several single base mutations within the human bgalactosidase gene have been identified in subtypes (15, 16). We have recently found three brothers with type 3 GM1 gangliosidosis presenting as dystonia. To clarify the pathogenesis of dystonia in this disorder, brain magnetic resonance imaging (MRI) was performed in addition to clinical analysis. Case reports and methods
The pedigree of the affected Japanese family is shown in Fig. 1. Each patient was the child of first cousins.
- A 28-year-old man, was the proband of the family. He was born after a normal pregnancy and delivery. His early development progressed nor-
Patient I.
mally until age 3, when his parents noticed difficulties in stammering and gait disturbance. These neurological abnormalities progressed slowly, and facial grimacing with dystonic postures in the limbs appeared 7 years later. At 22 years of age, he could not walk at all. On admission, he was bedridden in a state of dysphonia phonatorica, subluxation of the mandible, marked scoliosis, and joint contracture at the ankle secondary to severe dystonia. Communication was possible only by pointing to written words. He showed facial grimacing, torticollis, and marked dystonic postures and movements of the trunk and limbs. Both neck and limbs were stiff, and jaw jerk reflex was hyperactive. Other tendon stretch reflexes were normal, and a Chaddock sign was elicited on the left. Laboratory studies revealed a leukocyte count of 3600/mm3, a hemoglobin of 10.3 g/dl, and a hematocrit of 30.8%. The level of serum ceruloplasmin and copper were normal. In the cerebrospinal fluid (CSF), homovanillic acid (HVA) was 12.4 ng/dl (normal, 41.8-44.8), and 5-hydroxyindole-acetic acid was 22.1 ng/ml (normal, 11.2-29.2). Nerve conduction velocities and electroencephalogram (EEG) were normal. Needle electromyography (EMG) showed normal muscular units but surface EMG disclosed continuous, tonic, and non-reciprocal discharges in agonist and antagonist muscles. Radiographic studies of bones demonstrated flattening of the vertebral bodies with irregular intervertebral 609
Uyama et al. I
w @-&l-gl b b
111
k ''Ic* X '9&
0
IV IV
33y Patient 3
31y
Patient 2
I8y
Patient 1
a: a: 0 0: t
: Normal : Helerorygoles Affected
Helerorygoles
:Dead
Fig. 1. The pedigree of the family. Arrow indicates the proband of this family.
spaces. Cranial computed tomographic (CT) scan showed diffuse cerebral atrophy with dilated frontal horns of the lateral ventricles. Single photon emission computer assisted tomography using 123-iodinediethylene triamine pentaacetic acid revealed no significant perfusion defect. Patient 2. - was the 31-year-old elder brother of Patient 1. His early development was normal until age 3, when his parents noticed stammering and gait disturbance. Motor control deteriorated slowly but progressively, and he was unable to speak at age 7. Therefore, he could not complete elementary school. By age 22, he was totally confined to a wheelchair. Examination disclosed coarseness of the face, slight corneal opacities, and joint limitations. Intelligence was deteriorated, and his speech was limited to simple words. Facial grimacing with dystonia in the neck and limbs was easily elicited by emotional stress. Neither dystonic postures or movements resulting from varying degrees of fixed rigidity of each muscle involved did not disappear when the patient was lying or sitting relaxed. Tendon reflexes were slightly increased, but the Babinski sign was not observed. Routine laboratory studies were unremarkable except for mild leukopenia. X-ray examination of the vertebral bodies showed moderate platy spondylia. Patient 3. - the 33-year-old elder brother of Patients 1 and 2, was the product of a normal full-term pregnancy and delivery. He had normal psychological development until age 11, when walking abnormalities and speech difficulties became evident. At age 20, he developed intellectual impairment. Eleven years later, he underwent total hip replacement arthroplasty for osteoarthritis of the right hip with necrotic changes of the femoral head. On examination, he measured 1.65 m in height and weighed 54 kg. 610
Facial appearance was normal. The liver and spleen could not be felt. He was alert and intelligence was only mildly deteriorated. He could not move the tongue rapidly or speak fluently. There was no limb weakness or muscle atrophy. Muscle stretch reflexes were slightly increased. Facial grimacing and dystonia of the limbs were observed but they were milder than in Patients 1 and 2. Routine blood analysis and EEG were normal. Radiological studies of bones demonstrated moderate platyspondylia, especially at the lumbar level. CT scan disclosed moderate brain atrophy with widening of the frontal horns of the lateral ventricles. Enzyme assays - The procedures for enzyme assays were essentially the same as described previously (17, 18). The activity of p-galactosidase was determined by using 4-methylumbelliferyl (MU)+ galactoside as substrate. The activity of neuraminidase was measured with 4-MU-a-D-N-acetylneuraminic acid as substrate. The other lysosomal hydrolases were also assayed with 4-MU as substrates. The protein content of the enzyme sources was determined by the method of Lowry and coworkers (19). Ultrastructuralstudies - For electron microscopy, the major part of the bone marrow aspirate and rectal mucosa from Patient 1 were immediately fixed in 2.5% glutaraldehyde, and postfixed in 2% osmium tetroxide. The tissues were embedded in Epon 812 and sectioned as described previously (18). Magnetic resonance imaging - MRI scans were performed with a spin echo sequence on a 0.22-Tesla Signa unit for Patient 1 and on a 0.5-Tesla Signa unit for Patient 2. T1-weighted (TR = 500 msec; TE = 40 msec), proton density (TR = 2000 msec; TE = 40 msec), and T2-weighted (TR = 2000 msec; TE=80msec) images were obtained in the axial and coronal planes. In Patient 3, we did not perform MRI because of metal implantation in his right hip. Results
Enzyme activities - Acid 4-MU-pgalactosidase activities in cultured skin fibroblasts of Patient 1 and in the lymphocytes of Patients 1, 2, and 3 were decreased to about 5 % of the normal control (Fig. 2). The same activities in the parents were 50% to 70% of the control values. The activities of 4-MU-aneuraminidase in the lymphocytes of Patient 1 were normal; the activities of 4-MU-phexosaminidase A & B in cultured skin fibroblasts of Patient 1 and in the lymphocytes of all patients were also normal.
MRI findings in Type 3 GM1 gangliosidosis Drug therapyfor dystonia - Trials of diazepam up to a dose of 20 mg/day and L-DOPA up to 1 g/day for Patient 1 slightly improved the dystonia, but trihexyphenidyl up to 14 mg/day was not effective. Discussion
Fig. 2. pH activity curves of pgalactosidase in tissues from control, Patients 1, 2, and 3, and parents. Activities were measured with 4-methylumbelliferyl (MU)-pgalactoside as substrate. Values of 4-MU-pgalactosidase are expressed as nmol/mg protein/ hr.
Electron microscopy - Three kinds of intracytoplasmic membrane-limited inclusions were observed in macrophages. In the bone marrow, spindle- or irregular-shaped tubular structures composed of fine fibrils, about 50 nm in width were accumulated in several macrophages (Fig. 3a). In the rectal mucosa, most of the macrophages possessed a large number of clear vacuoles, about 1-2 pM in diameter, showing the appearance of foam cells (Fig. 3b). In a few macrophages in the rectal mucosa, round osmiophilic multilamellar concentric inclusions ranging 500 to 2000 nm in diameter were occasionally found (Fig. 3c). MRZfindings - The T1-weighted MRI showed diffuse brain atrophy, predominantly of the caudate nucleus and putamen in Patients 1 and 2. The ratio of the maximum bilateral ventricular diameter, FH/CC (20), was 1.68 in Patient 1 and 1.86 in Patient 2 (normal; 1.8-3.7). That of Patient 3 by X-ray CT was 2.23. The T2-weighted MRI demonstrated bilaterally symmetrical high intensity lesions only in the putamen in both Patients 1 and 2 (Figs. 4a, 4c). Such abnormalities were less evident but still observed on proton density images (Figs. 4b, 4d). Putaminal lesions could not be detected on T1weighted images.
We diagnosed GM 1 gangliosidosis based on the following data. Acid 4-MU-pgalactosidase activities in cultured skin fibroblasts of Patient 1 and in the lymphocytes of all three patients were reduced to about 5 % of the normal control value. The activities of 4-MU-pgalactosidase in the parents were 50% to 70% of normal value. The activities of other lysosomal enzymes including a-neuraminidase, were normal in lymphocytes of Patient 1. In addition, electron microscopic examinations disclosed membranelimited intracytoplasmic inclusions of lysosomal origin in macrophages obtained from the bone marrow and rectal mucosa as seen in cases previously reported ( 5 , 8). Furthermore, a specific and common mutation of the human pgalactosidase gene, 5 lZle(ATG)+ Thr(ACG), in Japanese patients with type 3 GM1 gangliosidosis had been identified in our patients (16). In this family, the most prominent and common neurological sign was generalized dystonia. In contrast to idiopathic dystonia (21,22), both dystonic postures and the movements resulting from varying degrees of fixed rigidity of each muscle involved failed to disappear when the patients were lying or sitting relaxed. This is characteristic of symptomatic dystonia (23). We also observed some degree of correlation between the severity of dystonia and that of brain atrophy among our patients. However, we found no correlation between the severity of dystonia and the residual activities of acid 4-MU-Pgalactosidase. To date, more than 20 patients with type 3 GM1 gangliosidosis have been reported in the literature (Table 1). Although the age of onset and the subsequent course were variable, dysarthria, which should result from dystonia, was commonly seen among them (2- 12). Subsequently, extrapyramidal signs such as limbs’ dystonia, choreoathetotic movements, plastic rigidity, or facial grimacing were frequently observed except in a few atypical cases (10). Neuropathologic study of type 3 GM1 gangliosidosis was performed in two cases, revealing that the intraneuronal storage of cytoplasmic membranous material was localized primarily in the neurons of basal ganglia including the caudate nucleus, putamen and globus pallidus (5, 6). This selective intraneuronal storage pattern, had been confirmed biochemically (13, 14). However, our neuroradiological study using MRI showed only putaminal lesions on T2-weighted and proton density images. Interest61 1
Uyama et al.
Fig. 3. Electron micrographs of macrophages obtained from Patient l . Three kinds of intracytoplasmic inclusions. (a) Tubular or fibrillar structures in bone marrow macrophage ( x 30000).
(b) Electron-lucent vacuoles in a macrophage of the rectal mucosa ( x 16000). (c) Concentric multilamelar structures in a macrophage of the rectal mucosa ( x 20000).
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MRI findings in Type 3 GM1 gangliosidosis
Fig. 4. Magnetic resonance scan of Patient 1 (a, b) and Patient 2 (c, d). (a, c) Axial T2-weighted images show bilaterally symmetrical high intensity lesions only in the putamen. (b, d) These characteristic findings are less evident but still observed on coronal proton density images.
ingly, this pattern of MRI was quite similar to the Japanese case reported by Inui and colleagues (12). The reason for selective putaminal lesions on MRI remains obscure, but we presume that the accumulation of GM1 ganglioside may be most prominent in the putamen which is well-known as the largest nucleus in the basal ganglia. Thus this pattern of MRI indicates that the putaminal changes may be the lesions most responsible for symptomatic dystonia in type 3 GM1 gangliosidosis. With the increasing availability of MRI, more reports of MRI findings in cases of metabolic diseases involving basal ganglia are being done. In Wilson
disease, bilaterally symmetrical areas of abnormal signal were seen in the lenticular, thalamic, caudate, and dentate nuclei, as well as in the brainstem (2426). Besides, a pattern of symmetrical hyperintense lesions on T2-weighted images involving the basal ganglia and brainstem, with predominant involvement of the putamen, is highly specific for subacute necrotizing encephalomyelopathy (Leigh syndrome) (27). In comparison with the MRI findings of our cases, the lesions should be frequently detected on T1-weighted images as low intensity lesions not localized in the putamen. MRI is also useful in the diagnosis of Hallervorden-Spatz syndrome, which is 613
Uyama et al. Table 1. Clinical features of type 3 GM, gangliosidosis
Author
Age
Sex
Suzuki (1977)
34y
F M M M M M F M M F M M F F F M F F F M M M M
30y Stevenson (19781
Wenger ( 1980) Goldman ( 198 1) Ohta (1983) Nakano (1985)
Ushiyama (1985) Mutoh (1986)
Guazzi (1988)
lnui ( 1990) Present cases
19y 27y 41y 19y 25y 27y 51y 38y 45y 43y 22y 54y 43y 27y 27y 24y 17y
32y 28y 31y 33y
Onset
Corneal opacity
Platyspondylia dysplastic dysplastic
t n.d.
t t t n.d.
t t
t
n.d. n.d. n.d.
t t t
t
Intellectual impairment
t t t (la461 t t (iQ43) t t t (1066)
t (1081) t (1063) t (1060) t (la601 t (IQ70) t t (1060) t (la81I t t t
Dysarthria
t t
t t t t t t
t t t t
t t t t t t t
t t t
t
Involuntary movement
Pyramidal sign
bs., gri. bs., gri. athetoid choreic athetoid dtstonia dystonia dystonia
t t t t t
dystonia dystonia dystonia dystonia myoclonus tremor myoclonus athetoid athetoid athetoid dystonia dystonia dystonia dystonia
t
References
t t t
-
t t
(91 (10)
t t t t t
(111
-
(12)
t t
t
n.d.: not done, b.s.: blephalospasm, gri.: grimacing
known as “eye-of-the-tiger” sign in the globus pallidus (28), and in GM2 gangliosidoses, which appears as symmetrical hypointense thalami on T2weighted images (29). Increased signal in the putamen on TZweighted images is also shown in patients with post-infarct dystonia, post-infectious dystonia, glutaric aciduria, and unclassified secondary dystonia (30). Thus, the pattern of MRI in our patients is not specific but characteristic for type 3 GM 1 gangliosidosis. In conclusion, MRI is clearly useful for assessing the involvement of basal ganglia in patients with type 3 GM 1 gangliosidosis. Selective putaminal changes on MRI may be the lesions most responsible for symptomatic dystonia characteristic of this disorder. Acknowledgements We thank Dr. Sadaaki Okamoto of the Department of Neurology, Musashigaoka Hospital, Kumamoto, and Dr. Kohei Ise of the Department of Orthopedics, Kumamoto Municipal Hospital, for providing the patients. We also wish to thank our colleague Dr. Mineharu Sugimoto, and Dr. Teruo Kitagawa of the Department of Pediatrics, Nihon University School of Medicine, Tokyo, for helpful advice.
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