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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Marinesco-Sjögren syndrome (MSS) is characterized by cerebellar ataxia with cerebellar atrophy, early-onset (not necessarily congenital) cataracts, mild to severe mental retardation, hypotonia, and muscle weakness. Additional features include short stature and various skeletal abnormalities including scoliosis. Children with MSS usually present with muscular hypotonia in early infancy; distal and proximal muscular weakness is noticed during the first decade of life. 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. Cataracts can develop rapidly and typically require lens extraction in the first decade of life. Although many adults are severely handicapped, life span in MSS seems to be near normal.
Diagnosis/testing. Diagnosis is based on clinical, radiographic, and neuroimaging studies. Electron-microscopic ultrastructural changes are thought to be specific to MSS. SIL1 is the only gene known to be associated with Marinesco-Sjögren syndrome. Molecular genetic testing is available clinically.
Management. Treatment of manifestations: symptomatic treatment of muscular manifestations usually by pediatric or adult neurologists and physiatrists and/or physical therapists; education programs tailored to the individual's developmental needs; cataract extraction as needed; hormone replacement therapy for primary gonadal failure at the expected time of puberty. Surveillance: regular follow-up with a child or adult neurologist and physiatrist and/or physical therapist; ophthalmologic examination at regular intervals beginning in infancy.
Genetic counseling. Marinesco-Sjögren syndrome (MSS) is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal testing using molecular genetic techniques may be available through laboratories offering custom prenatal testing.
Marinesco-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 [Williams et al 1996, 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 radiographic findings in bone are scoliosis; shortening of metacarpals, metatarsals, and phalanges; coxa valga; pes planovalgus; and pectus carinatum [Reinker et al 2002, Mahjneh et al 2006].
Serum 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].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. 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 testing
Sequence 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 summarizes molecular genetic testing for this disorder.
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|
| SIL1 | Sequence analysis 1 | Sequence variants | ~50%-60% | Clinical
 |
1. Exons sequenced may vary by laboratory. Exons 1 and 2 are not part of the coding region and may not be sequenced.
To 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
No other phenotypes are known to be associated with mutations in SIL1.
Infants 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 mental retardation.
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.
No genotype-phenotype correlations have been reported to date. It should be noted that the severity of mental retardation and myopathy vary widely among Finnish individuals, all of whom are homozygous for the same SIL1 mutation.
MSS has previously been called Garland-Moorhouse syndrome, Marinesco-Garland syndrome, and hereditary oligophrenic cerebello-lental degeneration.
Individuals first described as having Marinesco-Sjögren-like syndrome (also called ataxia-juvenile cataract-myopathy-mental retardation (OMIM 248810) were later found to have classic MSS with SIL1 mutations, resulting in discontinuation of this OMIM entry.
Prevalence is not known.
MSS is pan ethnic.
The carrier frequency in Finland is approximately 1:96.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
In 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]. CCFDN maps to chromosome 18qter [Angelicheva et al 1999]; mutations in CTDP1 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.
To 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 muscular manifestations is symptomatic. Affected individuals are usually managed by pediatric or adult neurologists and physiatrists and/or physical therapists.
Developmental delay and mental retardation 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.
Hormone replacement therapy in individuals with hypergonadotropic hypogonadism and reduced physical activity can prevent osteoporosis.
The 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
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Marinesco-Sjögren syndrome (MSS) is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. Affected individuals with hypergonadotropic hypogonadism (primary gonadal failure) are likely to be infertile and thus have no offspring.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members is available once the mutations have been identified in the family.
Family planning
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
No laboratories offering molecular genetic testing for prenatal diagnosis of Marinesco-Sjögren syndrome are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering custom prenatal testing, see
.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| SIL1 | 5q31 | Nucleotide exchange factor SIL1 |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| Gene Symbol | Entrez Gene |
|---|---|
| SIL1 | 64374 (MIM No. 608005) |
For a description of the genomic databases listed, click here.
Normal allelic variants. The main transcript of the SIL1 gene 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 17 mutations have been described in SIL1 (see Table 2; 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]. Most mutations are nonsense or frameshift mutations predicted to truncate the protein product. Splice site mutations and one missense mutation 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 the HSPA5 gene; 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 a truncated protein likely to make it nonfunctional or the transcript or the 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 only MSS-associated missense SIL1 mutation (c.1370T>C; p.L457P) (see Table 2; pdf) 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 [Todorov 1965]. Aside from the cerebellar defect, no muscle or lens phenotype was reported in the woozy mouse.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Marinesco-Sjogren Syndrome
Email: mss@marinesco-sjogren.org
www.marinesco-sjogren.org
WE MOVE (Worldwide Education and Awareness for Movement Disorders)
204 West 84th Street
New York NY 10024
Phone: 800-437-MOV2 (800-437-6683)
Fax: 212-875-8389
Email: wemove@wemove.org
www.wemove.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
7 October 2008 (cd) Revision: sequencing of select exons available on a clinical basis
29 November 2006 (me) Review posted to live Web site
6 July 2006 (ael) Original submission
