e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 1 9 9 e2 0 3

Official Journal of the European Paediatric Neurology Society

Original article

Marinesco-Sjögren syndrome due to SIL1 mutations with

a comment on the clinical phenotype

M. Horvers a,b, A.K. Anttonen c,g, A.E. Lehesjoki c, E. Morava d, S. Wortmann d, S. Vermeer e,
B.P. van de Warrenburg f, M.A. Willemsen a,*
a
Department of Paediatric Neurology, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour,
PO Box 9101, 6500HB Nijmegen, The Netherlands
b
Department of Neurology, Rijnstate Hospital, Arnhem, The Netherlands
c
Folkhälsan Institute of Genetics, Department of Medical Genetics, and Neuroscience Centre, University of Helsinki, Helsinki, Finland
d
Department of Pediatrics, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour,
Nijmegen, The Netherlands
e
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour,
Nijmegen, The Netherlands
f
Department of Neurology, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour,
Nijmegen, The Netherlands
g
Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland

article info abstract

Article history: Background: Marinesco-Sjögren syndrome is an autosomal recessive cerebellar ataxia,

Received 4 January 2012 characterised by cerebellar ataxia, myopathy, cataracts and intellectual disability, due to
Received in revised form mutations in the SIL1 gene.
7 September 2012 Methods: The clinical features and two novel SIL1 mutations of four Dutch patients with
Accepted 15 September 2012 Marinesco-Sjögren syndrome are described and compared to the literature on genetically
proven Marinesco-Sjögren patients.
Keywords: Results: The core phenotype of this syndrome appears homogeneous, but: [1] cataract can
Marinesco-Sjögren syndrome develop later than the motor and cognitive signs; [2] myopathy is an early feature that
SIL1 mutation seems progressive during the course of the disease; [3] serum creatine kinase is normal or
Clinical features only mildly elevated; [4] peripheral neuropathy is absent; and [5] a variable degree of
intellectual disability is present in most Marinesco-Sjögren patients.
Conclusions: Because the late appearance of some hallmarks and the uncertainty as to
whether incomplete phenotypes occur, SIL1 mutation analysis is helpful early in the
diagnostic work-up of children with suspected inherited ataxias.
ª 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
reserved.

* Corresponding author. Tel.: þ31 24 3614654; fax: þ31 24 3617018.

E-mail address: m.willemsen@neuro.umcn.nl (M.A. Willemsen).
1090-3798/$ e see front matter ª 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejpn.2012.09.007
200 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 1 9 9 e2 0 3

1. Introduction consanguineous. All patients were born after an uncompli-

cated pregnancy and delivery and presented in the first year of
Among the hereditary ataxias, autosomal recessive cerebellar life with delayed achievement of motor milestones. Ability to
ataxias (ARCA’s) are a heterogeneous group of complex neuro- walk was finally achieved within the first decade and gait was
degenerative disorders, of which Friedreich’s ataxia (MIM ataxic in all patients. Currently, all patients are able to walk
#229300) is generally considered the prototype. Clinically, independently in their home environment, but use a wheel-
ARCA’s are characterised by progressive cerebellar syndromes chair for longer distances. In all four patients, bilateral cata-
and e depending on the precise disorder involved e other racts developed and progressed rapidly between the ages of
neurological and extra-neurological signs and symptoms. Diag- three and five years and were surgically removed. Secondary
nosing the underlying ARCA in individual patients is notoriously cataract developed in patients MSS3 and MSS4 and necessi-
difficult due to the heterogeneity among these disorders.1 tated another operation at the age of 19 years. All patients had
Marinesco-Sjögren syndrome (MSS; MIM #248800) is one of muscle weakness, with proximal and distal muscles equally
the ARCA’s, characterised by early-onset ataxia with cerebellar affected, skeletal deformities and mild to moderate intellec-
atrophy, cataracts, intellectual disability, and myopathic tual disability. In the older patients, gait appeared much more
features. Additional features that can appear are hyper- disabled by muscle weakness than cerebellar ataxia. Magnetic
gonadotropic hypogonadism, skeletal abnormalities, and short resonance imaging demonstrated cerebellar atrophy in all
stature. Recently, SIL1 mutations were shown to cause MSS.2e4 patients (Fig. 1). In MSS3 and MSS4, muscle biopsy showed
SIL1 is a glycoprotein that is present in the endoplasmic retic- mild non-specific abnormalities, and lacked the typical
ulum (ER) and plays an important role as co-chaperone in protein features as described in other MSS patients (see below).
translocation into the ER, protein folding, controlling the degra-
dation of misfolded proteins, and responding to cell stress.5,6 As 3.2. Genetic analysis
a consequence, mutations in SIL1 lead to disturbance in proper
folding of proteins and subsequently cell destruction. We detected a novel homozygous nonsense mutation
Here, we describe four Dutch patients from 2 separate c.1060C > T (p.Gln354X) in patients MSS1 and MSS2. MSS3 and
families with genetically proven MSS including two novel SIL1 MSS4 were compound heterozygotes for a novel missense
mutations. In addition, we review the genetically confirmed mutation c.935G > A (p.Gly312Glu) and a previously described
MSS patients reported in literature so far, with emphasis on splice site mutation c.645þ2T > C. PolyPhen analysis predicted
the clinical signs and symptoms at onset and during the the c.935G > A missense mutation to be probably damaging.
further course of the disease. The parents of both families were heterozygous carriers of
a mutation and the three different mutations detected in the
patients were absent in 186 control chromosomes. None of the
2. Methods mutations found were present in the 1000 genomes (www.
1000genomes.org) or Exome Variant Server databases.12
2.1. Study patients
3.3. MSS patients with SIL1 mutations in the literature
We describe the clinical, radiological and biochemical findings (n ¼ 64)
of two pairs of siblings from separate Dutch families with the
clinical diagnosis of MSS. Mutation analysis of the SIL1 gene Patients’ characteristics are outlined in Table 1 and Table 2. In
was performed using the methods as previously described.3 38 out of the 64 patients information about disease onset was
2.2. MSS patients with SIL1 mutations in the literature available. Reported onset was usually between the ages of two
to four years. Most reports describe first presentation with
We reviewed all available published reports on MSS and SIL1 global developmental delay or an unstable gait. Two patients
mutations, ascertained by a PubMed search using the showed no ataxia and in three other patients that were
keywords: Marinesco-Sjögren syndrome AND SIL1. We found wheelchair bound, information on the presence or absence of
11 hits and the following 8 reports that matched our criteria: ataxia could not be retrieved. Except for one patient (aged 1.2
Senderek et al. [2005]; Anttonen et al. [2005]; Karim et al. years), all patients developed cataract.
[2006]; Annesi et al. [2007]; Anttonen et al. [2008]; Eriguchi et al.
[2008]; Riazuddin et al. [2009]; Takahata et al. [2010].3,4,6e11 For
the purpose of this study we systematically reviewed the 4. Discussion
literature concerning the clinical course and additional labo-
ratory and radiologic examinations. Our patients exhibited obvious ataxia, similar to more than
90% of MSS patients with SIL1 mutations in literature. Only
two patients without ataxia have been reported, however the
3. Results respective patients have not been examined by the authors
themselves.11 A previous study reviewing 125 case reports
3.1. Study patients with a clinical diagnosis of MSS found ataxia in 98% of cases.13
Cerebellar ataxia seems to be a core feature in MSS due to SIL1
Patients’ characteristics are outlined in Table 1. To their mutations and generally occurs early in life, with onset at
knowledge, the parents in both families were not preschool age.
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 1 9 9 e2 0 3 201

Table 1 e Study patients and review patients characteristics.

Familiy A Familiy B Literature

Patient MSS 1 MSS 2 MSS 3 MSS 4 n ¼ 64

Sex, Age (years) M, 9.8 M, 7 M 39.1 M, 38.2 31 F/33 M
Mutation Homozygous Homozygous c.935G > A and c.935G > A and (See Table 2)
c.1060C > T c.1060C > T c.645þ2T > C c.645þ2T > C
Presenting Marked hypotonia Global Hypotonia since birth, Poor head balance
symptom (age) since age of 10 developmental global developmental as a baby and
months, global delay, titubation delay global developmental
developmental at 8 months delay
delay.
Central nervous
system
Ataxia þ þ þ þ 59/64
Nystagmus þ þ þ þ 34/46
Mental retardation (IQ) þ þ þ þ
Dysartria  (Speech þ þ (Mild) þ (Mild)
difficulties
because of
schizis)
MRI (cerebellar þ þ þ þ 43/43
atrophy)
Ocular symptoms
Cataract (age in years) þ (4) þ (4) þ (4 and 20) þ(3 and 19) 63/64 (0e7)
Neuromuscular
symptoms
Hypotonia, paresis, þ þ þ þ 52/52
atrophy
Elevated serum CK  (169) ND þ (311)  (72) 39/47
(reference < 220 u/l)
Myopathy (EMG þ ND þ þ 41/42
or biopsy)
Skeletal symptoms
Skeletal Deformities þ (Mild scoliosis, þ (Pes þ (Mild scoliosis) þ (Severe scoliosis) 26/46
Stature in cm (SD) pes planovalgus) planovalgus) 177 (1) 172.5 (1;2) 39/55
118.5 (<2.5) 108 (<2.5)
Endocrine disorders
Hypogonadism NDa NDa þ þ 24/32

a ND: not determined.

Another key feature in MSS is cataract, traditionally re- childhood, often with a quite sudden onset and rapidly
ported to be ‘congenital’. Our cases and the results of the progressive course.3,14,15 The diagnosis of MSS should thus not
literature review, however, clearly show that cataract is be excluded on clinical grounds in infants and young children
generally absent in young infants and appears later in with a cerebellar syndrome but lacking cataract.

Fig. 1 e Saggital T1 weighted MR images at the age of 13 months (left; patient MSS 2) and 7.5 years (right; patient MSS 1),
illustrating the cerebellar atrophy, already occurring early during the course of the disease.
202 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 1 9 9 e2 0 3

MSS cases do not have craniofacial dysmorphism in strictu

Table 2 e Reported mutations in the SIL1 gene.
sensu.14
Exon Nucleotide Amino acid Reference Elevated levels of serum creatine kinase (CK) was present
change change
in one of our patients (MSS3) and in 39 of 47 SIL1 mutation
4
Exon 3 c.178C > T p.E60X positive patients, with the highest level found only being two-
3
Exon 3 c.212dupA p.H71QfsX5 and-a-half times the upper level of normal. Thus, high serum
9
Exon 4 c.274C > T p.R92W CK levels are certainly not an obligatory finding in MSS and, if
3,4,8
Exon 4 c.331C > T p.R111X
4
elevated at all, levels are only mildly increased.
Exon 4 c.346delG p.G116fs
10 MRI displayed marked cerebellar atrophy in all MSS
Exon 6-7 c.454-?_767þ?del 58-kb deletion
Exon 6 c.506_509dupAAGA p.D170EfsX4 3 patients with SIL1 mutations. Additional, but only incidentally
Exon 6 c.603_607delGAAGA p.E200DfsX6 10 reported neuroradiologic features include supratentorial
4
Exon 6 c.645þ1G > A Skipping exon 6 cortical atrophy and non-specific white matter lesions, and
3
Exon 6 c.645þ2T > C p.V186_Q215del , This paper abnormalities of the pituitary gland.19,20
p.A152_Q215del Curative treatment strategies for MSS are currently not
Exon 9 c.935G > A p.G312E This paper
6,7 available, thus treatment is supportive and based on symp-
Exon 9 c.936dupG p.L313AfsX39
Exon 9 c.947_948insT p.L316fs 4 tomatic relief by physical therapy, education programs for
Exon 9 c.1029þ1G > A Skipping exon 9 4 developmental needs, cataract extraction, and hormonal
Exon 9 c.1030-18G > A p.L344fs 4
replacement therapy in case of hypogonadism.
6
Exon 9 c.1030-9G > A p.F345AfsX9 Patients with an MSS-like phenotype but without SIL1
Exon 10 c.1060C > T p.Q354X This paper mutations have been described. Although these patients
9
Exon 10 c.1240C > T p.Q414X
4
generally did not exhibit all core clinical features, the possi-
Exon 10 c.1249C > T p.Q417X
11 bility of genetic heterogeneity has still been raised.5,6 On the
Exon 10 c.1312C > T p.Q438X
Exon 10 c.1366delT p.L456fs 4 other hand, patients with SIL1 mutations but without the
Exon 10 c.1367T > A p.L456X 6 classical phenotype have been published, implying the exis-
Exon 10 c.1370T > C p.L457P 6
tence of at least some clinical heterogeneity.11

Neuromuscular features like hypotonia, muscle weakness Conclusion

and atrophy occur early in MSS. Muscle histology may show
rimmed vacuolar myopathic features and ragged red fibers, Although SIL1 positive MSS appears to be a homogeneous
although not present in all patients.16,17 Muscle imaging may disorder with ataxia, cataract, myopathic features, intellec-
show extensive replacement of muscle tissue with fat and tual disability and hypogonadism, we would like to emphasize
connective tissue.16 Interestingly, peripheral neuropathy is [1] that cataract can develop later than the motor and cogni-
not reported in patients with SIL1 mutations. In view of the tive signs; [2] that myopathy occurs early in childhood and
differential diagnosis of the ARCA’s this is an important clue seems progressive during the course of the disease; [3] and
since many other ARCA’s are accompanied by (axonal) that serum CK is normal or only mildly elevated. Obviously,
neuropathies. In agreement with previous observations,16,17 hypogonadism, although clinically relevant, is usually not
we found it difficult to estimate the relative contribution of a helpful sign in the differential diagnosis because of its
the cerebellar and myopathic disorder to the motor distur- appearance after the first decade of life. More helpful is the
bances in our patients, but nevertheless had the strong absence of peripheral neuropathy and the finding of a variable
impression that the coordination disorder had been stable degree of intellectual disability in patients with MSS. Overall,
during the course of the disease while muscle weakness and the full-blown phenotype of MSS will be recognizable among
atrophy progressed gradually. patients with ARCA on clinical grounds. Given the late
In all four patients, intellectual ability was mildly to appearance of some of the hallmarks of MSS, and because it is
moderately impaired, which is in agreement with previous not clear yet in which frequency deviant phenotypes occur,
reports that describe a high prevalence of intellectual we advise to consider SIL1 mutation analysis early in the
disability in MSS.13 It is important to not that intellectual diagnostic work-up of children with suspected ARCA, partic-
disability is generally not a part of the more common other ularly if intellectual disability is present.
ARCA’s.
Additional features such as hypergonadotropic hypo-
gonadism and skeletal deformities (i.e. scoliosis, gracile and Financial support
short bones, et cetera) were present in our patients as well as
in previous literature. Although most skeletal abnormalities Nothing to disclose.
are likely to develop secondary to motor disturbances, it is still
a matter of debate whether primary bone abnormalities are
part of MSS.18
One study patient (MSS1) had a cleft palate. Slavotinek Conflict of interest
et al. reviewed the literature with focus on dysmorphic
features in MSS and concluded that the majority of reported None to declare.
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 1 9 9 e2 0 3 203

9. Riazuddin SA, miri-Kordestani L, Kaul H, Butt T, Jiao X,

Acknowledgement Riazuddin S, et al. Novel SIL1 mutations in consanguineous
Pakistani families mapping to chromosomes 5q31. Mol Vis
The authors wish to thank the patient and their parents, and 2009;15:1050e6.
the healthcare professionals involved for referring the 10. Takahata T, Yamada K, Yamada Y, Ono S, Kinoshita A,
Matsuzaka T, et al. Novel mutations in the SIL1 gene in
patients to our centre.
a Japanese pedigree with the Marinesco-Sjogren syndrome.
J Hum Genet 2010;55:142e6.
references 11. Karim MA, Parsian AJ, Cleves MA, Bracey J, Elsayed MS,
Elsobky E, et al. A novel mutation in BAP/SIL1 gene causes
Marinesco-Sjogren syndrome in an extended pedigree. Clin
1. Vermeer S, van de Warrenburg BP, Willemsen MA, Genet 2006;70:420e3.
Cluitmans M, Scheffer H, Kremer BP, et al. Autosomal 12. Exome Variant Server. Nhlbi GO Exome sequencing project (ESP).
recessive cerebellar ataxias: the current state of affairs. J Med Seattle, WA, http://evs.gs.washington.edu/EVS/; 2012
Genet 2011;48:651e9. [4.9.2012 accessed]. Ref type: Generic.
2. Lagier-Tourenne C, Tranebaerg L, Chaigne D, Gribaa M, 13. Williams TE, Buchhalter JR, Sussman MD. Cerebellar
Dollfus H, Silvestri G, et al. Homozygosity mapping of dysplasia and unilateral cataract in Marinesco-Sjogren
Marinesco-Sjogren syndrome to 5q31. Eur J Hum Genet syndrome. Pediatr Neurol 1996;14:158e61.
2003;11:770e8. 14. Slavotinek A, Goldman J, Weisiger K, Kostiner D, Golabi M,
3. Anttonen AK, Mahjneh I, Hamalainen RH, Lagier-Tourenne C, Packman S, et al. Marinesco-Sjogren syndrome in a male
Kopra O, Waris L, et al. The gene disrupted in Marinesco- with mild dysmorphism. Am J Med Genet A
Sjogren syndrome encodes SIL1, an HSPA5 cochaperone. Nat 2005;133A:197e201.
Genet 2005;37:1309e11. 15. Ishikawa T, Kitoh H, Awaya A, Nonaka I. Rapid cataract
4. Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, formation in Marinesco-Sjogren syndrome. Pediatr Neurol
Breitbach-Faller N, et al. Mutations in SIL1 cause Marinesco- 1993;9:407e8.
Sjogren syndrome, a cerebellar ataxia with cataract and 16. Mahjneh I, Anttonen AK, Somer M, Paetau A, Lehesjoki AE,
myopathy. Nat Genet 2005;37:1312e4. Somer H, et al. Myopathy is a prominent feature in
5. Chung KT, Shen Y, Hendershot LM. BAP, a mammalian BiP- Marinesco-Sjogren syndrome: a muscle computed
associated protein, is a nucleotide exchange factor that tomography study. J Neurol 2006;253:301e6.
regulates the ATPase activity of BiP. J Biol Chem 17. Komiyama A, Nonaka I, Hirayama K. Muscle pathology
2002;277:47557e63. in Marinesco-Sjogren syndrome. J Neurol Sci
6. Anttonen AK, Siintola E, Tranebjaerg L, Iwata NK, Bijlsma EK, 1989;89:103e13.
Meguro H, et al. Novel SIL1 mutations and exclusion of 18. Reinker K, Hsia YE, Rimoin DL, Henry G, Yuen J, Powell B, et al.
functional candidate genes in Marinesco-Sjogren syndrome. Orthopaedic manifestations of Marinesco-Sjogren syndrome.
Eur J Hum Genet 2008;16:961e9. J Pediatr Orthop 2002;22:399e403.
7. Eriguchi M, Mizuta H, Kurohara K, Fujitake J, Kuroda Y. 19. McLaughlin JF, Pagon RA, Weinberger E, Haas JE. Marinesco-
Identification of a new homozygous frameshift insertion Sjogren syndrome: clinical and magnetic resonance imaging
mutation in the SIL1 gene in 3 Japanese patients with features in three children. Dev Med Child Neurol
Marinesco-Sjogren syndrome. J Neurol Sci 2008;270:197e200. 1996;38:363e70.
8. Annesi G, Aguglia U, Tarantino P, Annesi F, De Marco EV, 20. Reinhold A, Scheer I, Lehmann R, Neumann LM, Michael T,
Civitelli D, et al. SIL1 and SARA2 mutations in Marinesco- Varon R, et al. MR imaging features in Marinesco-Sjogren
Sjogren and chylomicron retention diseases. Clin Genet syndrome: severe cerebellar atrophy is not an obligatory
2007;71:288e9. finding. AJNR Am J Neuroradiol 2003;24:825e8.