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Title: SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome
Authors: Krieger, Michael ×
Roos, Andreas
Stendel, Claudia
Claeys, Kristl
Sonmez, Fatma Mujgan
Baudis, Michael
Bauer, Peter
Bornemann, Antje
de Goede, Christian
Dufke, Andreas
Finkel, Richard S
Goebel, Hans H
Häussler, Martin
Kingston, Helen
Kirschner, Janbernd
Medne, Livija
Muschke, Petra
Rivier, François
Rudnik-Schöneborn, Sabine
Spengler, Sabrina
Inzana, Francesca
Stanzial, Franco
Benedicenti, Francesco
Synofzik, Matthis
Lia Taratuto, Ana
Pirra, Laura
Tay, Stacey Kiat-Hong
Topaloglu, Haluk
Uyanik, Gökhan
Wand, Dorothea
Williams, Denise
Zerres, Klaus
Weis, Joachim
Senderek, Jan #
Issue Date: Dec-2013
Publisher: Macmillan
Series Title: Brain vol:136 issue:Pt 12
Article number: 10.1093/brain/awt283
Abstract: Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjögren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expression.
URI: 
ISSN: 0006-8950
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Faculty of Medicine - miscellaneous
× corresponding author
# (joint) last author

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