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Identification of a new homozygous frameshift insertion mutation in the SIL1 gene in 3 Japanese patients with Marinesco–Sjögren syndrome
Journal of the Neurological Sciences 270 (2008) 197 – 200 www.elsevier.com/locate/jns
Short communication
Identification of a new homozygous frameshift insertion mutation in the SIL1 gene in 3 Japanese patients with Marinesco–Sjögren syndrome Makoto Eriguchi a , Haruo Mizuta a,⁎, Kazuhiro Kurohara b , Junko Fujitake c , Yasuo Kuroda a a
Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan b Department of Neurology, Saga Shakai-hoken Hospital, Saga, Japan c Department of Neurology, Kyoto City Hospital, Kyoto, Japan
Received 2 October 2007; received in revised form 5 February 2008; accepted 7 February 2008 Available online 18 April 2008
Abstract Marinesco–Sjögren syndrome (MSS) is an autosomal recessive multisystem disorder characterized by cerebellar ataxia, cataracts, progressive muscular weakness, and developmental and mental retardation. Recently, mutations in the SIL1 gene on chromosome 5q31 have been shown to be a cause of MSS. We sequenced the entire SIL1-coding region in 3 unrelated Japanese patients with classical MSS and identified a novel homozygous frameshift insertion mutation, 936_937insG, in exon 9 in all 3 patients. © 2008 Elsevier B.V. All rights reserved. Keywords: Marinesco–Sjögren syndrome; SIL1 gene; Mutation; Autosomal recessive disease; Cerebellar atrophy; Mental retardation; Cataract; Loss-of-function
1. Introduction Marinesco–Sjögren syndrome (MSS) is a rare autosomal recessive multisystem disorder. The cardinal features of MSS are cerebellar ataxia, cataracts, short stature, and mental retardation [1–3], though it may also be present with hypergonadotrophic hypogonadism, skeletal abnormalities, dysmorphism, epilepsy, progressive myopathy, or neuropathy [1–3]. Recently, mutations in the SIL1 gene on chromosome 5q31 have been shown to cause MSS [4–7]. However, MSS is considered a clinically and genetically heterogeneous disorder, since SIL1 gene mutations are not always found in patients with classical MSS [5] and have been found in no patients with atypical MSS [5,8]. We therefore sequenced all 10 exons of the SIL1 gene in 3 unrelated Japanese patients with classical MSS, and identi-
⁎ Corresponding author. Department of Internal Medicine, Faculty of Medicine, Saga University, 849-8501 Saga, Japan. Tel.: +81 952 34 2353; fax: +81 952 34 2017. E-mail address: [email protected] (H. Mizuta). 0022-510X/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2008.02.012
fied a new frameshift insertion mutation, 936_937insG, in exon 9 of the SIL1 gene in all three. 2. Methods 2.1. Patients We analyzed the SIL1 gene in 3 Japanese patients with clinically definite MSS. The diagnosis of MSS was made based on clinical and neuroradiological features. Analysis of the SIL1 gene was approved by the review board for medical ethics of the Faculty of Medicine of Saga University. Because all 3 patients had mental retardation, written informed consent was obtained from each patient's parent(s) and/or sibling(s). 2.2. Sequencing DNA was prepared from whole blood using standard protocols. We obtained primer sequences for the SIL1 gene from Dr. Senderek [5]. The coding exons and flanking intronic sequences were amplified and sequenced according to methods described in the initial report of SIL1 gene mutations
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M. Eriguchi et al. / Journal of the Neurological Sciences 270 (2008) 197–200
Table 1 Clinical genetic characterization of individuals with MSS and SIL1 mutations
age Consanguinity(degree) sex Short statue Cataract Psychomotor delay Ataxia Myopathy convulsion Cerebellar atrophy Mutation
MSS 1
MSS 2
MSS 3
38 − M + + + + + − + 936_937ins G exon 9
45 − M + + + + + + + 936_937ins G exon 9
48 +(2nd) F + + + + + + + 936_937ins G exon 9
using genomic DNA [5]. We sequenced all 10 SIL1 exons and their surrounding intronic borders. The purified products of PCR amplification were sequenced from both directions on automated sequencers (ABI 310; Applied Biosystems, Foster City, CA) using the ABI Prism Bidgye Terminator Cycle sequencing kit, as recommended by the manufacturer.
3. Results The age of each patient at neurological and neuroradiological examinations is shown in the Table 1. Clinically, all 3 patients presented with key features of MSS, including cerebellar ataxia, infantile-onset cataracts, mental retardation, and short stature (Table 1). MRI of the brain revealed marked atrophy of the cerebellum, especially the vermis, in all three (Fig. 1). In addition, one patient had hypergonadotrophic hypogonadism, two had generalized convulsive seizures, and all had muscular weakness due to myopathy, as demonstrated by electromyography and MRI of the muscles (Supplementary figure). Pedigrees of the three patients are shown in Fig. 2. The family name and permanent domicile differed among the three patients, and no information indicating kinship between them was obtained. A loop of consanguinity was demonstrated only in one family, but familial occurrence of MSS was found for none of them. Sequencing of the entire SIL1-coding region showed that all the 3 MSS patients carried the same homozygous mutation, insertion of G at the position 936_937 in exon 9 (Fig. 3), which had not been reported previously.
Fig. 1. Brain MRI of 3 Japanese patients with classical MSS. Marked atrophy of the cerebellum is found in all three.
M. Eriguchi et al. / Journal of the Neurological Sciences 270 (2008) 197–200
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Fig. 2. Pedigrees of 3 Japanese patients with classical MSS. No kinship is present between Family 1 and Family 3.
4. Discussion
Fig. 3. Sequencing of genomic DNA showing the homozygous 936_937insG insertion mutation.L313. Arrows indicate the site of insertion.
In 2005, two groups independently found mutations in the SIL1 gene that cause MSS. Anttonen et al. [4] studied 8 classical MSS patients and identified SIL1 gene mutations in all of them. Importantly, the mutations segregated with disease phenotype in families. They reported that all of four Finnish patients and one Norwegian patient carried homozygous 4nucleotide duplication (506_509dupAAGA) in exon 6, and that a Swedish patient had this 506_509dupAAGA mutation in compound heterozygosis [4]. The other two patients, of Turkish and of French origin, carried different homozygous mutations. Senderek et al. [5] analyzed SIL1 gene in both classical and atypical MSS patients of various ethnic origins, and identified several SIL1 gene mutations such as premature stop codons, frame shifts, disruption of donor splice sites, and a single nucleotide substitution in homozygosis or compound heterozygosis in 11 of 15 classical MSS patients [5]. However, none of the remaining 4 patients with classical MSS and 5 patients with atypical MSS had mutations in the SIL1 gene [5]. Notably, both studies revealed a homozygous SIL1 gene mutation with 331C→T substitution in Turkish MSS patients [4,5]. The presence of SIL1 gene mutations in patients with classical MSS was subsequently confirmed in consanguineous Italian and Egyptian families by other groups [6,7]. In the present study, we analyzed all 10 exons of the SIL1 gene in 3 unrelated Japanese patients who exhibited all of the key features of classical MSS, and identified a novel homozygous insertion of G at the position 936_937 in exon 9 in all 3 patients. This mutation has not been found in other
200
M. Eriguchi et al. / Journal of the Neurological Sciences 270 (2008) 197–200
ethnic populations, consistent with previous findings of differences in mutation of the SIL1 gene among ethic/racial populations [4,5]. The SIL1 gene encodes a 461-amino acid protein that is present in the endoplasmic reticulum (ER), a central site of protein synthesis and protein quality control [9–12]. SIL1 is important for protein translocation to the ER and acts as a nucleotide exchange factor for the ER chaperone protein BiP, which is required for the proper folding of proteins [9–12]. SIL1 acts to release BiP from proteins after BiP has facilitated their folding. Thus, mutations of the SIL1 gene are predicted to cause loss-of-function resulting in misfolding and dysfunction of many proteins [10]. Loss-of-function was shown by immunostaining for SIL1 in skeletal muscle biopsies of MSS patients, which failed to reveal its presence [4]. In addition, a mouse model of MSS, the woozy mouse, which exhibits progressive ataxia with loss of Purkinje cells, was shown to have a homozygous mutation of the SIL1 gene [13]. In the woozy mouse, loss-of-function of SIL1 results in abnormal accumulation of ubiquinated proteins in cerebellar Purkinje cells, followed by neurodegeneration characterized by both apoptosis and autophagy [13]. Our two patients had generalized epilepsy, which is occasionally observed in MSS patients [1–3]. SIL1 is expressed in cortical neurons as well as in cerebellar Purkinje cells [4], and cerebral abnormalities such as atrophy and white matter involvement have been reported in MSS[14,15]. Thus, in addition to mental retardation, epilepsy might be considered an essential cerebral manifestation of MSS. In conclusion, we identified a new homozygous insertion mutation, 936_937insG, in the SIL1 gene of 3 unrelated Japanese patients with classical MSS. Our findings support the hypotheses that SIL1 gene mutation causes classical MSS and that differences exist in mutation of the SIL1 gene among ethic/racial populations. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jns.2008.02.012.
References [1] Alter M, Talbert OR, Croffead G. Cerebellar ataxia, congenital cataracts, and retarded somatic and mental maturation. Neurology 1962;12:836–47. [2] Mahloudji M. Marinesco–Sjögren syndrome. In: Vinken PJ , Bruyn GW, editors. Handbook of Clinical Neurology, vol. 21. Amsterdam: NorthHolland; 1975. p. 555–61. [3] Slavotinek A, Goldman J, Weisiger K, Kostiner D, Golabi M, Packman S, et al. Marinesco–Sjögren syndrome in a male with mild dysmorphism. Am J Med Genet 2005;133A:197–201. [4] Anttonen AK, Mahjneh I, Hämäläinen RH, Lagier-Tourenne C, Kopra O, Waris L, et al. The gene disrupted in Marinesco–Sjögren syndrome encodes SIL1, an HSPA5 cochaperone. Nat Genet 2005;37:1309–11. [5] Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, BreitbachFaller N, et al. Mutations in SIL1 cause Marinesco–Sjögren syndrome, a cerebellar ataxia with cataract and myopathy. Nat Genet 2005;37:1312–4. [6] Karim MA, Parsian AJ, Cleves MA, Bracey J, Elsayed MS, Elsobky E, et al. A novel mutation in BAP/SIL1 gene causes Marinesco–Sjögren syndrome in an extended pedigree. Clin Genet 2006;70:420–3. [7] Annesi G, Aguglia U, Tarantino P, Annesi F, De Marco EV, Civitelli D, et al. SIL1 and SARA2 mutations in Marinesco–Sjögren and chylomicron retention diseases. Clin Genet 2007;71:288–9. [8] Schulz S, Vielhaber S, Muschke P, Mohnike K, Gooding R, Wieacker P. Congenital cataract, ataxia, external ophthalmoplegia and dysphagia in two siblings. A Marinesco–Sjögren -like syndrome. Neuropediatrics 2007;38:88–90. [9] Zoghbi HY. SILencing misbehaving proteins. Nat Genet 2005;37:1302–3. [10] van Raamsdonk JM. Loss of function mutations in SIL1 cause Marinesco–Sjögren syndrome. Clin Genet 2006;69:399–403. [11] Weitzmann A, Baldes C, Dudek J, Zimmermann R. The heat shock protein 70 molecular chaperone network in the pancreatic endoplasmic reticulum. FEBS J 2007;274:5175–87. [12] Ni M, Lee AS. ER chaperones in mammalian development and human diseases. FEBS Lett 2007;581:3641–51. [13] Zhao L, Longo-Guess C, Harris BS, Lee JW, Ackerman SL. Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Nat Genet 2005;37:974–9. [14] Bromberg MB, Junck L, Gebarski SS, McLean MJ, Gilman S. The Marinesco–Sjögren syndrome examined by computed tomography, magnetic resonance, and 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography. Arch Neurol 1990;47:1239–42. [15] Reinhold A, Scheer I, Lehmann R, Neumann LM, Michael T, Varon R, et al. MR imaging features in Marinesco–Sjögren syndrome: severe cerebellar atrophy is not an obligatory finding. Am J Neuroradiol 2003;24:825–8.
Short communication
Identification of a new homozygous frameshift insertion mutation in the SIL1 gene in 3 Japanese patients with Marinesco–Sjögren syndrome Makoto Eriguchi a , Haruo Mizuta a,⁎, Kazuhiro Kurohara b , Junko Fujitake c , Yasuo Kuroda a a
Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan b Department of Neurology, Saga Shakai-hoken Hospital, Saga, Japan c Department of Neurology, Kyoto City Hospital, Kyoto, Japan
Received 2 October 2007; received in revised form 5 February 2008; accepted 7 February 2008 Available online 18 April 2008
Abstract Marinesco–Sjögren syndrome (MSS) is an autosomal recessive multisystem disorder characterized by cerebellar ataxia, cataracts, progressive muscular weakness, and developmental and mental retardation. Recently, mutations in the SIL1 gene on chromosome 5q31 have been shown to be a cause of MSS. We sequenced the entire SIL1-coding region in 3 unrelated Japanese patients with classical MSS and identified a novel homozygous frameshift insertion mutation, 936_937insG, in exon 9 in all 3 patients. © 2008 Elsevier B.V. All rights reserved. Keywords: Marinesco–Sjögren syndrome; SIL1 gene; Mutation; Autosomal recessive disease; Cerebellar atrophy; Mental retardation; Cataract; Loss-of-function
1. Introduction Marinesco–Sjögren syndrome (MSS) is a rare autosomal recessive multisystem disorder. The cardinal features of MSS are cerebellar ataxia, cataracts, short stature, and mental retardation [1–3], though it may also be present with hypergonadotrophic hypogonadism, skeletal abnormalities, dysmorphism, epilepsy, progressive myopathy, or neuropathy [1–3]. Recently, mutations in the SIL1 gene on chromosome 5q31 have been shown to cause MSS [4–7]. However, MSS is considered a clinically and genetically heterogeneous disorder, since SIL1 gene mutations are not always found in patients with classical MSS [5] and have been found in no patients with atypical MSS [5,8]. We therefore sequenced all 10 exons of the SIL1 gene in 3 unrelated Japanese patients with classical MSS, and identi-
⁎ Corresponding author. Department of Internal Medicine, Faculty of Medicine, Saga University, 849-8501 Saga, Japan. Tel.: +81 952 34 2353; fax: +81 952 34 2017. E-mail address: [email protected] (H. Mizuta). 0022-510X/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2008.02.012
fied a new frameshift insertion mutation, 936_937insG, in exon 9 of the SIL1 gene in all three. 2. Methods 2.1. Patients We analyzed the SIL1 gene in 3 Japanese patients with clinically definite MSS. The diagnosis of MSS was made based on clinical and neuroradiological features. Analysis of the SIL1 gene was approved by the review board for medical ethics of the Faculty of Medicine of Saga University. Because all 3 patients had mental retardation, written informed consent was obtained from each patient's parent(s) and/or sibling(s). 2.2. Sequencing DNA was prepared from whole blood using standard protocols. We obtained primer sequences for the SIL1 gene from Dr. Senderek [5]. The coding exons and flanking intronic sequences were amplified and sequenced according to methods described in the initial report of SIL1 gene mutations
198
M. Eriguchi et al. / Journal of the Neurological Sciences 270 (2008) 197–200
Table 1 Clinical genetic characterization of individuals with MSS and SIL1 mutations
age Consanguinity(degree) sex Short statue Cataract Psychomotor delay Ataxia Myopathy convulsion Cerebellar atrophy Mutation
MSS 1
MSS 2
MSS 3
38 − M + + + + + − + 936_937ins G exon 9
45 − M + + + + + + + 936_937ins G exon 9
48 +(2nd) F + + + + + + + 936_937ins G exon 9
using genomic DNA [5]. We sequenced all 10 SIL1 exons and their surrounding intronic borders. The purified products of PCR amplification were sequenced from both directions on automated sequencers (ABI 310; Applied Biosystems, Foster City, CA) using the ABI Prism Bidgye Terminator Cycle sequencing kit, as recommended by the manufacturer.
3. Results The age of each patient at neurological and neuroradiological examinations is shown in the Table 1. Clinically, all 3 patients presented with key features of MSS, including cerebellar ataxia, infantile-onset cataracts, mental retardation, and short stature (Table 1). MRI of the brain revealed marked atrophy of the cerebellum, especially the vermis, in all three (Fig. 1). In addition, one patient had hypergonadotrophic hypogonadism, two had generalized convulsive seizures, and all had muscular weakness due to myopathy, as demonstrated by electromyography and MRI of the muscles (Supplementary figure). Pedigrees of the three patients are shown in Fig. 2. The family name and permanent domicile differed among the three patients, and no information indicating kinship between them was obtained. A loop of consanguinity was demonstrated only in one family, but familial occurrence of MSS was found for none of them. Sequencing of the entire SIL1-coding region showed that all the 3 MSS patients carried the same homozygous mutation, insertion of G at the position 936_937 in exon 9 (Fig. 3), which had not been reported previously.
Fig. 1. Brain MRI of 3 Japanese patients with classical MSS. Marked atrophy of the cerebellum is found in all three.
M. Eriguchi et al. / Journal of the Neurological Sciences 270 (2008) 197–200
199
Fig. 2. Pedigrees of 3 Japanese patients with classical MSS. No kinship is present between Family 1 and Family 3.
4. Discussion
Fig. 3. Sequencing of genomic DNA showing the homozygous 936_937insG insertion mutation.L313. Arrows indicate the site of insertion.
In 2005, two groups independently found mutations in the SIL1 gene that cause MSS. Anttonen et al. [4] studied 8 classical MSS patients and identified SIL1 gene mutations in all of them. Importantly, the mutations segregated with disease phenotype in families. They reported that all of four Finnish patients and one Norwegian patient carried homozygous 4nucleotide duplication (506_509dupAAGA) in exon 6, and that a Swedish patient had this 506_509dupAAGA mutation in compound heterozygosis [4]. The other two patients, of Turkish and of French origin, carried different homozygous mutations. Senderek et al. [5] analyzed SIL1 gene in both classical and atypical MSS patients of various ethnic origins, and identified several SIL1 gene mutations such as premature stop codons, frame shifts, disruption of donor splice sites, and a single nucleotide substitution in homozygosis or compound heterozygosis in 11 of 15 classical MSS patients [5]. However, none of the remaining 4 patients with classical MSS and 5 patients with atypical MSS had mutations in the SIL1 gene [5]. Notably, both studies revealed a homozygous SIL1 gene mutation with 331C→T substitution in Turkish MSS patients [4,5]. The presence of SIL1 gene mutations in patients with classical MSS was subsequently confirmed in consanguineous Italian and Egyptian families by other groups [6,7]. In the present study, we analyzed all 10 exons of the SIL1 gene in 3 unrelated Japanese patients who exhibited all of the key features of classical MSS, and identified a novel homozygous insertion of G at the position 936_937 in exon 9 in all 3 patients. This mutation has not been found in other
200
M. Eriguchi et al. / Journal of the Neurological Sciences 270 (2008) 197–200
ethnic populations, consistent with previous findings of differences in mutation of the SIL1 gene among ethic/racial populations [4,5]. The SIL1 gene encodes a 461-amino acid protein that is present in the endoplasmic reticulum (ER), a central site of protein synthesis and protein quality control [9–12]. SIL1 is important for protein translocation to the ER and acts as a nucleotide exchange factor for the ER chaperone protein BiP, which is required for the proper folding of proteins [9–12]. SIL1 acts to release BiP from proteins after BiP has facilitated their folding. Thus, mutations of the SIL1 gene are predicted to cause loss-of-function resulting in misfolding and dysfunction of many proteins [10]. Loss-of-function was shown by immunostaining for SIL1 in skeletal muscle biopsies of MSS patients, which failed to reveal its presence [4]. In addition, a mouse model of MSS, the woozy mouse, which exhibits progressive ataxia with loss of Purkinje cells, was shown to have a homozygous mutation of the SIL1 gene [13]. In the woozy mouse, loss-of-function of SIL1 results in abnormal accumulation of ubiquinated proteins in cerebellar Purkinje cells, followed by neurodegeneration characterized by both apoptosis and autophagy [13]. Our two patients had generalized epilepsy, which is occasionally observed in MSS patients [1–3]. SIL1 is expressed in cortical neurons as well as in cerebellar Purkinje cells [4], and cerebral abnormalities such as atrophy and white matter involvement have been reported in MSS[14,15]. Thus, in addition to mental retardation, epilepsy might be considered an essential cerebral manifestation of MSS. In conclusion, we identified a new homozygous insertion mutation, 936_937insG, in the SIL1 gene of 3 unrelated Japanese patients with classical MSS. Our findings support the hypotheses that SIL1 gene mutation causes classical MSS and that differences exist in mutation of the SIL1 gene among ethic/racial populations. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jns.2008.02.012.
References [1] Alter M, Talbert OR, Croffead G. Cerebellar ataxia, congenital cataracts, and retarded somatic and mental maturation. Neurology 1962;12:836–47. [2] Mahloudji M. Marinesco–Sjögren syndrome. In: Vinken PJ , Bruyn GW, editors. Handbook of Clinical Neurology, vol. 21. Amsterdam: NorthHolland; 1975. p. 555–61. [3] Slavotinek A, Goldman J, Weisiger K, Kostiner D, Golabi M, Packman S, et al. Marinesco–Sjögren syndrome in a male with mild dysmorphism. Am J Med Genet 2005;133A:197–201. [4] Anttonen AK, Mahjneh I, Hämäläinen RH, Lagier-Tourenne C, Kopra O, Waris L, et al. The gene disrupted in Marinesco–Sjögren syndrome encodes SIL1, an HSPA5 cochaperone. Nat Genet 2005;37:1309–11. [5] Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, BreitbachFaller N, et al. Mutations in SIL1 cause Marinesco–Sjögren syndrome, a cerebellar ataxia with cataract and myopathy. Nat Genet 2005;37:1312–4. [6] Karim MA, Parsian AJ, Cleves MA, Bracey J, Elsayed MS, Elsobky E, et al. A novel mutation in BAP/SIL1 gene causes Marinesco–Sjögren syndrome in an extended pedigree. Clin Genet 2006;70:420–3. [7] Annesi G, Aguglia U, Tarantino P, Annesi F, De Marco EV, Civitelli D, et al. SIL1 and SARA2 mutations in Marinesco–Sjögren and chylomicron retention diseases. Clin Genet 2007;71:288–9. [8] Schulz S, Vielhaber S, Muschke P, Mohnike K, Gooding R, Wieacker P. Congenital cataract, ataxia, external ophthalmoplegia and dysphagia in two siblings. A Marinesco–Sjögren -like syndrome. Neuropediatrics 2007;38:88–90. [9] Zoghbi HY. SILencing misbehaving proteins. Nat Genet 2005;37:1302–3. [10] van Raamsdonk JM. Loss of function mutations in SIL1 cause Marinesco–Sjögren syndrome. Clin Genet 2006;69:399–403. [11] Weitzmann A, Baldes C, Dudek J, Zimmermann R. The heat shock protein 70 molecular chaperone network in the pancreatic endoplasmic reticulum. FEBS J 2007;274:5175–87. [12] Ni M, Lee AS. ER chaperones in mammalian development and human diseases. FEBS Lett 2007;581:3641–51. [13] Zhao L, Longo-Guess C, Harris BS, Lee JW, Ackerman SL. Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Nat Genet 2005;37:974–9. [14] Bromberg MB, Junck L, Gebarski SS, McLean MJ, Gilman S. The Marinesco–Sjögren syndrome examined by computed tomography, magnetic resonance, and 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography. Arch Neurol 1990;47:1239–42. [15] Reinhold A, Scheer I, Lehmann R, Neumann LM, Michael T, Varon R, et al. MR imaging features in Marinesco–Sjögren syndrome: severe cerebellar atrophy is not an obligatory finding. Am J Neuroradiol 2003;24:825–8.