Marinesco-Sjögren Syndrome
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 nystagmusMRI. 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 biopsyLight microscopy. Variation in muscle fiber size, atrophic fibers, fatty replacement, and rimmed vacuole formation on light microscopyElectron 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:
- Single-gene testing. Sequence analysis of SIL1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- 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 at the most reasonable cost 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
| 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.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Author, personal observation; Senderek et al [2005]; Krieger et al [2013]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available; four larger deletions involving different exons of SIL1 have been reported to date [Takahata et al 2010, Krieger et al 2013, Nair et al 2016].
- 7.
Some individuals with typical Marinesco-Sjögren syndrome do not have identifiable pathogenic variants in SIL1, implying the existence of other as-yet-unknown genes [Senderek et al 2005, Krieger et al 2013, Goto et al 2014].
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:
- Normal to moderately elevated serum creatine kinase (CK) levels
- Myopathic changes on EMG
- Nonspecific findings on muscle biopsy by light microscopy (variation in muscle fiber size, atrophic fibers, fatty replacement, and rimmed vacuole formation [Herva et al 1987, Suzuki et al 1997])
- Findings specific to MSS on muscle biopsy by electron microscopy (autophagic vacuoles, membranous whorls, and electron-dense double-membrane structures associated with nuclei) [Krieger et al 2013]
- Severe dystrophy-type muscle tissue replacement with fat and connective tissue seen on muscle imaging studies [Mahjneh et al 2006]
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]
- A T2-hyperintense cerebellar cortex in individuals with molecularly confirmed MSS [Harting et al 2004, Anttonen et al 2005]
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.
Genotype-Phenotype Correlations
No 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 with MSS, all of whom are homozygous for the same SIL1 pathogenic variant.
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.
MSS is pan ethnic.
The carrier frequency in Finland has been reported to be approximately 1:96, compared to ~1/700 in a pan ethnic population [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)
| Disorder | Gene(s) | MOI | Clinical Features of This Disorder | ||
|---|---|---|---|---|---|
| Overlapping with MSS | Distinguishing from MSS | Other | |||
| Congenital cataracts, facial dysmorphism, and neuropathy syndrome (CCFDN) | CTDP1 | AR |
|
| To date, CCFDN has only been reported in persons of Roma (Gypsy) ethnicity. |
| GBA2-related Marinesco-Sjögren syndrome-like disorder 1 | GBA2 | AR |
|
| |
| VLDLR-associated cerebellar hypoplasia | VLDLR | AR |
|
| |
| Cerebral amyloid angiopathy, ITM2B-related, 2 (OMIM 117300) | ITM2B | AD |
|
| |
| Muscular dystrophy, congenital, w/cataracts & ID (OMIM 617404) | INPP5K | AR |
|
| |
| Mitochondrial disorders (See Mitochondrial Disorders Overview.) |
|
| |||
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance
- 1.
Haugarvoll et al [2017]
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
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.