Marinesco-Sjögren Syndrome
Anna-Kaisa Anttonen, MD, PhD.
Author Information and AffiliationsInitial Posting: November 29, 2006; Last Update: January 10, 2019.
Estimated reading time: 15 minutes
Summary
Clinical characteristics.
Marinesco-Sjögren syndrome (MSS) is characterized by cerebellar ataxia with cerebellar atrophy, dysarthria, nystagmus, early-onset (not necessarily congenital) cataracts, myopathy, muscle weakness, and hypotonia. Additional features may include psychomotor delay, hypergonadotropic hypogonadism, short stature, and various skeletal abnormalities. 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, nystagmus, 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 have severe disabilities, life span in MSS appears to be near normal.
Diagnosis/testing.
Diagnosis is established in an individual with typical clinical findings and/or biallelic pathogenic variants of SIL1 identified on molecular genetic testing. Electron-microscopic ultrastructural changes on muscle biopsy are thought to be specific to MSS.
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 pathogenic variant. 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. Carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible if the pathogenic variants in the family are known.
Diagnosis
Suggestive Findings
Marinesco-Sjögren syndrome (MSS) should be suspected in individuals with the following clinical findings:
Cerebellar ataxia with cerebellar atrophy, dysarthria, and nystagmus
MRI. Cerebellar atrophy, usually more pronounced in the vermis than the hemispheres
Early-onset (not necessarily
congenital) cataracts
Myopathy, muscle weakness, and hypotonia
Serum CK concentration. Normal or moderately increased (usually 2-4x upper-normal limits)
EMG. Myopathic features only
Muscle biopsy
Light microscopy. Variation in muscle fiber size, atrophic fibers, fatty replacement, and rimmed vacuole formation on light microscopy
Electron microscopy. Autophagic vacuoles, membranous whorls, and electron-dense double-membrane structures associated with nuclei (a specific ultrastructural feature of MSS) [
Krieger et al 2013]
Additional features variably present:
Psychomotor delay
Hypergonadotropic hypogonadism (i.e., primary gonadal failure)
Short stature
Various skeletal abnormalities including scoliosis; shortening of metacarpals, metatarsals, and phalanges; coxa valga; pes planovalgus; and pectus carinatum
Establishing the Diagnosis
The diagnosis of MSS is established in a proband with typical clinical findings and/or by identification of biallelic pathogenic variants in SIL1 on molecular genetic testing (see Table 1). Electron-microscopic ultrastructural changes on muscle biopsy are thought to be specific to MSS.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive
genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MSS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical findings in whom the diagnosis of MSS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of MSS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
A multigene panel that includes
SIL1 and other genes of interest (see
Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of
uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see
Table 1).
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Option 2
When the diagnosis of MSS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Marinesco-Sjögren Syndrome
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| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
|---|
|
SIL1
| Sequence analysis 3 | ~50%-60% 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 |
| Unknown 7 | NA | |
- 1.
- 2.
- 3.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
- 7.
Clinical Characteristics
Clinical Description
Infants with Marinesco-Sjögren syndrome (MSS) are born after uncomplicated pregnancies.
Neuromuscular concerns. 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, nystagmus, and dysarthria become apparent. Motor function worsens progressively for some years, then stabilizes at an unpredictable age and degree of severity.
Laboratory tests and imaging show the following:
Neuroimaging studies such as magnetic resonance imaging (MRI) show the following:
Cerebellar atrophy, usually more pronounced in the vermis than the hemispheres [
Harting et al 2004]
It is not known at what age the cerebellar atrophy begins; the youngest individuals with MSS who were studied with MRI were preschool age. Although the cerebellar atrophy is expected to be progressive, this has not been confirmed with repeated MRIs [Author, personal observation].
Ophthalmologic. Bilateral cataracts are not necessarily congenital and can develop rapidly. The mean age at onset of cataracts has been studied in two groups of affected individuals and was around 3.5 years [Krieger et al 2013, Goto et al 2014]. Cataracts typically required lens extraction in the first decade of life. Strabismus is present in at least half of the individuals reported with MSS [Goto et al 2014].
Atypical findings. 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 different disorder [Lagier-Tourenne et al 2003, Slavotinek et al 2005].
Developmental milestones are often delayed. Intellectual abilities vary from normal to severe intellectual disability.
Endocrinologic. Hypergonadotropic hypogonadism and delayed puberty are frequent findings [Anttonen et al 2005, Anttonen et al 2008, Krieger et al 2013], but no associated congenital genital anomalies have been described.
Growth. Many individuals with MSS have short stature [Anttonen et al 2005, Anttonen et al 2008]. Microcephaly has occasionally been reported [Krieger et al 2013].
Skeletal findings. A variable degree of scoliosis is common. 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]. The severity of the skeletal findings appears to correlate with the overall severity of manifestations [Mahjneh et al 2006].
Life span. Although many adults have severe disabilities, the life span associated with MSS appears to be near normal.
Nomenclature
Previously used terms for Marinesco-Sjögren syndrome:
Garland-Moorhouse syndrome
Marinesco-Garland syndrome
Hereditary oligophrenic cerebello-lental degeneration
Individuals first described as having Marinesco-Sjögren-like syndrome (also called ataxia-juvenile cataract-myopathy-intellectual disability [OMIM 248810]) were later found to have classic MSS with SIL1 pathogenic variants, resulting in discontinuation of this OMIM entry.
Prevalence
Prevalence is not known. The carrier frequency in Finland has been reported to be approximately 1:96, compared to an estimated worldwide carrier frequency of 1:700 [Lek et al 2016].
Differential Diagnosis
In individuals with atypical features of Marinesco-Sjögren syndrome (MSS), the differential diagnostic possibilities that should be considered are listed in Table 2.
Table 2.
Disorders to Consider in the Differential Diagnosis of Marinesco-Sjögren Syndrome (MSS)
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| DiffDx Disorder | Gene(s) | MOI | Clinical Features of DiffDx Disorder |
|---|
| Overlapping with MSS | Distinguishing from MSS |
|---|
| Congenital cataracts, facial dysmorphism, and neuropathy syndrome (CCFDN) 1 |
CTDP1
| AR | Cataracts DD Short stature Hypogonadism
|
|
| GBA2-related Marinesco-Sjögren syndrome-like disorder 2 |
GBA2
| AR | Ataxia developing in early childhood Normal early psychomotor development; however, mild progressive cognitive decline accompanies the other progressive CNS findings. Bilateral cataracts observed later in disease course.
|
|
|
VLDLR-associated cerebellar hypoplasia
|
VLDLR
| AR |
|
|
| Cerebral amyloid angiopathy, ITM2B-related, 2 (OMIM 117300) |
ITM2B
| AD |
| Absence of symptoms in childhood Absence of cerebellar atrophy Cataracts & ataxia later in onset than in MSS Presence of dementia (or psychosis)
|
| Muscular dystrophy, congenital, w/cataracts & ID (OMIM 617404) |
INPP5K
| AR |
|
|
| Mitochondrial disorders (See Mitochondrial Disorders Overview.) |
| Encephalopathy, seizures, dementia, migraine, & stroke-like episodes often present ↑ concentration of lactate Cardiomyopathy
|
- 1.
To date, CCFDN has only been reported in persons of Roma ethnicity.
- 2.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Marinesco-Sjögren syndrome (MSS), the following evaluations are recommended if they have not already been completed:
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 any needed therapies
Assessment of speech and feeding
Ophthalmologic examination
Endocrinologic evaluation
Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
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 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. Such therapy can help to prevent osteoporosis.
Surveillance
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
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Marinesco-Sjögren syndrome (MSS) is inherited in an autosomal recessive manner.
Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the SIL1 pathogenic variants in the family.
Prenatal Testing and Preimplantation Genetic Testing
Once the SIL1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Marinesco-Sjogren Syndrome
Email: mss@marinesco-sjogren.org
National Library of Medicine Genetics Home Reference
Molecular Genetics
Information 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 Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Gene structure. 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.
Pathogenic variants. More than 40 pathogenic variants have been described in SIL1 [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, Terracciano et al 2012, Krieger et al 2013, Goto et al 2014, Inaguma et al 2014, Cerami et al 2015, Noreau et al 2015, Gai et al 2016, Nair et al 2016]. Most pathogenic variants are nonsense or frameshift variants predicted to truncate the protein product. Splice site variants, missense variants, and a larger genomic deletion have also been described.
Normal gene product.
SIL1 encodes nucleotide exchange factor SIL1 (also known as BAP [BiP-associated protein]) for the endoplasmic reticulum (ER) 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 pathogenic variants 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 variants 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].
In transiently transfected COS-1 cells, a MSS-associated missense SIL1 variant formed aggregates within the ER, implying that aggregation of the variant protein may contribute to MSS pathogenesis. Similar aggregations were found while studying an artificial pathogenic variant 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 (wz) mutant mouse [Zhao et al 2005]. In the woozy mouse, the cerebellar Purkinje neuron degeneration is similar to that seen in MSS. More recently, a progressive myopathy with vacuolar and myonuclear alterations in the woozy mouse has been shown to cause a phenotype remarkably similar to human muscle [Roos et al 2014]. In addition, SIL1 has been shown to be involved in neuronal morphology and migration and axon network formation during mouse brain development [Inaguma et al 2014].
Chapter Notes
Author History
Anna-Kaisa Anttonen, MD, PhD (2006-present)
Anna-Elina Lehesjoki, MD, PhD; University of Helsinki (2006-2019)
Revision History
10 January 2019 (ha) Comprehensive update posted live
7 September 2010 (me) Comprehensive update posted live
7 October 2008 (cd) Revision: sequencing of select exons clinically available
29 November 2006 (me) Review posted live
6 July 2006 (ael) Original submission
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