DiagnosisClinical DiagnosisMarinesco-Sjögren syndrome (MSS) should be considered in individuals with the following clinical findings:Cerebellar ataxia with cerebellar atrophy Early-onset (not necessarily congenital) cataracts Psychomotor delay Myopathy, muscle weakness, and hypotonia Additional features:Hypergonadotropic hypogonadism (i.e., primary gonadal failure) Short stature Various skeletal abnormalities Dysarthria Strabismus and nystagmus Although atypical findings including optic atrophy and peripheral neuropathy have been reported, it is unknown whether these are rare manifestations of MSS or features of a distinct disorder [Lagier-Tourenne et al 2003, Slavotinek et al 2005].Electromyography (EMG). EMG typically shows myopathic features only. Imaging. In individuals with classic MSS, neuroimaging studies such as magnetic resonance imaging (MRI) show cerebellar atrophy, usually more pronounced in the vermis than the hemispheres [Harting et al 2004]. A T₂-hyperintense cerebellar cortex has been reported in individuals with MSS who have SIL1 mutations [Harting et al 2004, Anttonen et al 2005]. Muscle imaging studies show severe dystrophy-type muscle tissue replacement with fat and connective tissue [Mahjneh et al 2006].The usual skeletal radiographic findings are scoliosis; shortening of metacarpals, metatarsals, and phalanges; coxa valga; pes planovalgus; and pectus carinatum [Reinker et al 2002, Mahjneh et al 2006]. TestingSerum creatine kinase (CK) concentration. Serum CK concentrations are normal or moderately increased (usually 2-4 times the upper normal limits). Muscle biopsy. Light microscopy shows variation in muscle fiber size, atrophic fibers, fatty replacement, and rimmed vacuole formation [Herva et al 1987, Suzuki et al 1997]. Electron microscopy reveals autophagic vacuoles, membranous whorls, and electron-dense double-membrane structures associated with nuclei, which are thought to be a specific ultrastructural feature of MSS [Herva et al 1987, Sewry et al 1988, Sasaki et al 1996].Molecular Genetic TestingGene. SIL1 is the only gene known to be associated with MSS. Other loci. Some individuals with typical Marinesco-Sjögren syndrome do not have identifiable mutations in SIL1, implying the existence of other as-yet unknown genes [Senderek et al 2005]. Clinical testingSequence analysis. Direct sequencing of the SIL1 coding region and exon-intron boundaries detects mutations in approximately 50% of individuals fulfilling diagnostic criteria [Author, personal observation]. In an analysis of individuals with classic MSS only, Senderek et al [2005] found SIL1 mutations in 66% of families. Table 1. Summary of Molecular Genetic Testing Used in Marinesco-Sjögren SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ¹ Test AvailabilitySIL1Sequence analysis Sequence variants ^{2~50%-60%ClinicalSequence analysis of select exons Sequence variants in selected exons 2, 3UnknownDeletion/duplication analysis 4Partial- or whole-gene deletions or duplicationsUnknown 51. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.2. Small intragenic deletions/insertions, missense, nonsense, and splice site mutations.3. Exons sequenced may vary by laboratory. Exons 1 and 2 are not part of the coding region and may not be sequenced.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.5. Mutation detection frequency is unknown; only one large deletion involving SIL1 has been reported to date [Takahata et al 2010] Testing StrategyTo confirm/establish the diagnosis in a proband Clinical evaluation Brain MRI to evaluate for cerebellar atrophy Muscle biopsy and/or EMG to evaluate for typical myopathic features Molecular genetic testing starting with sequence analysis of SIL1 and followed by deletion/duplication analysis; since myopathic features are not easily detected in children, molecular genetic testing can be performed prior to muscle biopsy or EMG. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in SIL1.}

Natural HistoryInfants with Marinesco-Sjögren syndrome (MSS) are born after uncomplicated pregnancies. Muscular hypotonia is usually present in early infancy. Distal and proximal muscular weakness is noticed during the first decade of life. Many affected individuals are never able to walk without assistance. Later, cerebellar findings of truncal ataxia, dysdiadochokinesia, and dysarthria become apparent. Motor function worsens progressively for some years, then stabilizes at an unpredictable age and degree of severity.Bilateral cataracts are not necessarily congenital but can develop rapidly, typically requiring lens extraction in the first decade of life. Nystagmus and strabismus are present.Developmental milestones are delayed. Intellectual abilities vary from mild to severe intellectual disability. Many individuals with MSS have short stature and variable degrees of scoliosis. The severity of the skeletal findings seems to correlate with the overall severity of manifestations [Mahjneh et al 2006]. Although many adults are severely handicapped, the life span in MSS seems to be near normal.

Genotype-Phenotype CorrelationsNo genotype-phenotype correlations have been reported to date. It should be noted that the severity of intellectual disability and myopathy vary widely among Finnish individuals, all of whom are homozygous for the same SIL1 mutation.

Differential DiagnosisIn individuals with atypical features of Marinesco-Sjögren syndrome (MSS), the following differential diagnostic possibilities should be considered: Congenital cataracts, facial dysmorphism, and neuropathy syndrome (CCFDN) (OMIM 604168), which shares with MSS the features of cataracts, developmental delay, short stature, and hypogonadism [Kalaydjieva 2006]. The presence of (1) marked cerebellar atrophy leading to severe ataxia with myopathy in MSS and (2) hypo- or demyelinating neuropathy and post-infectious rhabdomyolysis in CCFDN distinguishes the two syndromes [Lagier-Tourenne et al 2002]. So far, CCFDN has only been reported in persons of Roma (Gypsy) ethnicity [Kalaydjieva 2006]. Mutations in CTDP1 on chromosome 18qter are causative [Varon et al 2003]. Ataxia-microcephaly-cataract syndrome (OMIM 208870), in which microcephaly distinguishes the phenotype from MSS Cataract-ataxia-deafness-retardation syndrome (OMIM 212710), which differs from MSS by the presence of sensorineural hearing loss and polyneuropathy VLDLR-associated cerebellar hypoplasia (OMIM 224050), in which progressive myopathy and elevated serum creatine kinase concentration are not seen Familial Danish dementia (OMIM 117300), a dominant disorder in which cataracts and ataxia are later in onset than in MSS and dementia or psychosis is also observed Other syndromes that share the main clinical features with MSS are clearly distinguishable on the basis of additional features.

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Marinesco-Sjögren syndrome (MSS), the following evaluations are recommended:Physical examination including measurement of height, weight, and head circumference Evaluation of motor skills with special attention to muscle strength and cerebellar function Assessment of developmental milestones in infants and intellectual abilities in older children, particularly before school age, to plan appropriate education and rehabilitation Assessment of speech and feeding Ophthalmologic examination Treatment of ManifestationsTreatment of muscular manifestations is symptomatic. Affected individuals are usually managed by pediatric or adult neurologists and physiatrists and/or physical therapists.Developmental delay and intellectual disability are managed with education programs tailored to the individual's needs.Cataracts are removed surgically during the first decade of life.Hypergonadotropic hypogonadism (i.e., primary gonadal failure) is treated with hormone replacement therapy at the expected time of puberty.Prevention of Secondary ComplicationsHormone replacement therapy in individuals with hypergonadotropic hypogonadism and reduced physical activity can prevent osteoporosis. SurveillanceThe following are appropriate:Regular follow-up with a child or adult neurologist and physiatrist and/or physical therapist If the diagnosis is made prior to the development of cataracts, ophthalmologic examination beginning in infancy and at regular intervals Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Marinesco-Sjogren Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSIL15q31​.2Nucleotide exchange factor SIL1SIL1 @ LOVDSIL1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Marinesco-Sjogren Syndrome (View All in OMIM) View in own window 248800MARINESCO-SJOGREN SYNDROME; MSS 608005SIL1, S. CEREVISIAE, HOMOLOG OF; SIL1Normal allelic variants. The primary transcript of SIL1 has ten exons and encodes a 461-amino acid protein. Northern blot analysis shows a transcript of approximately 1.8 kb in multiple tissues [Chung et al 2002, Anttonen et al 2005]. SIL1 can be alternatively spliced; a variant missing exon 6 is present in multiple tissues at low levels [Anttonen et al 2005] and another variant with an additional 5’ noncoding exon is present at least in placental tissue. Pathologic allelic variants. A total of 21 mutations have been described in SIL1 (see Table 2. Pathologic Allelic Variants in SIL1; pdf) [Anttonen et al 2005, Senderek et al 2005, Karim et al 2006, Annesi et al 2007, Anttonen et al 2008, Eriguchi et al 2008, Riazuddin et al 2009, Takahata et al 2010]. Most mutations are nonsense or frameshift mutations predicted to truncate the protein product. Splice site mutations, missense mutations, and a larger genomic deletion have also been described. Normal gene product. SIL1 encodes nucleotide exchange factor SIL1 (also known as BAP, for BiP-associated protein) for the endoplasmic reticulum resident heat-shock protein 70 chaperone BiP (also known as GRP78) [Tyson & Stirling 2000, Chung et al 2002]. As a nucleotide exchange factor, SIL1 induces ADP release and ATP binding of BiP. BiP is encoded by HSPA5; it functions in protein translocation, synthesis, and quality control and senses and responds to stressful cellular conditions [Hendershot 2004]. Marinesco-Sjögren syndrome (MSS) thus joins the group of protein-processing diseases. Abnormal gene product. Most of the MSS-associated SIL1 mutations predict protein truncation likely to render the protein nonfunctional or to cause the transcript or protein to be degraded. The consequence of the three splice site mutations reported in intron 6 and intron 9, resulting in in-frame deleted SIL1 variants, could be either incorrect folding or absence of important functional domains [Anttonen et al 2005, Senderek et al 2005]. In persons who have in-frame deleted SIL1 variants, immunohistochemical staining is present, indicating that the variant(s) are translated [Anttonen et al 2005]. The MSS-associated missense SIL1 mutation (NM_001037633.1:c.1370T>C)(p.Leu457Pro) (see Table 2) has been studied in more detail [Anttonen et al 2008]. In transiently transfected COS-1 cells the mutant formed aggregates within the ER implying that aggregation of the mutant protein may contribute to MSS pathogenesis. Similar aggregations were found while studying an artificial mutation deleting the last four amino acids (the putative ER retrieval signal) of SIL1 [Anttonen et al 2008].A truncation of Sil1 was shown to cause ataxia and cerebellar Purkinje cell loss in naturally-occurring woozy mutant mouse [Zhao et al 2005]. In the woozy mouse, the cerebellar Purkinje neuron degeneration is similar to that seen in MSS. Aside from the cerebellar defect, no muscle or lens phenotype was reported in the woozy mouse.