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.

The diagnosis of MSS is established in an individual with typical clinical findings and/or biallelic pathogenic variants in SIL1 identified by 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; developmental support and education programs tailored to the individual's developmental needs; cataract extraction as needed; treatment of strabismus per ophthalmologist; hormone replacement therapy for primary gonadal failure at the expected time of puberty; feeding support as needed for poor weight gain; management of scoliosis and other skeletal manifestations per orthopedist.

Surveillance: Assessment by child or adult neurologist and physiatrist and/or physical therapist annually or as needed; monitor developmental progress and educational needs at each visit; annual ophthalmologic examination beginning in infancy; monitor pubertal development throughout adolescence per endocrinologist; assess growth and feeding at each visit; clinical assessment for scoliosis at each visit, with radiographs as needed.

Genetic counseling.

MSS is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an MSS-related pathogenic variant. If both parents are known to be heterozygous for a SIL1 pathogenic variant, each sib of an affected individual has at conception 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. If biallelic SIL1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

MSS should be suspected in probands with the following findings.

Clinical findings

• Cerebellar ataxia, dysarthria, and nystagmus
• Early-onset (not necessarily congenital) cataracts
• Muscle weakness and hypotonia
• Psychomotor delay
• Hypergonadotropic hypogonadism (i.e., primary gonadal failure)
• Short stature
• Skeletal abnormalities (scoliosis; shortening of metacarpals, metatarsals, and phalanges; coxa valga; pes planovalgus; and pectus carinatum)

Imaging findings

• Brain MRI. Cerebellar atrophy, usually more pronounced in the vermis than the hemispheres and a T₂-hyperintense cerebellar cortex [Harting et al 2004, Anttonen et al 2005]. Note: Age of onset for cerebellar atrophy is unknown; the youngest individuals evaluated with brain MRI have been toddlers [Krieger et al 2013]. Although the cerebellar atrophy is expected to be progressive, this has not been confirmed with repeated MRIs [A-K Anttonen, personal observation].
• Muscle imaging studies. Severe dystrophy-type muscle tissue replacement with fat and connective tissue [Mahjneh et al 2006]

Laboratory findings. Normal or moderately increased serum creatine kinase concentration (usually 2-4 times upper-normal limits)

EMG findings. Myopathic features only

Muscle biopsy findings

• Light microscopy. Nonspecific findings including variation in muscle fiber size, atrophic fibers, fatty replacement, and rimmed vacuole formation [Herva et al 1987, Suzuki et al 1997]
• 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]

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Clinical diagnosis. The clinical diagnosis of MSS can be established in a proband with suggestive findings including characteristic ultrastructural changes on electron microscopy of a muscle biopsy thought to be specific to MSS.

Molecular diagnosis. The molecular diagnosis of MSS is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in SIL1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic SIL1 variants of uncertain significance (or of one known SIL1 pathogenic variant and one SIL1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Marinesco-Sjögren syndrome (MSS) is characterized by cerebellar ataxia, dysarthria, nystagmus, early-onset cataracts, hypotonia, and muscle weakness. Additional features may include psychomotor delay, hypergonadotropic hypogonadism, short stature, and skeletal abnormalities. To date, at least 140 individuals have been identified with biallelic pathogenic variants 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, Ezgu et al 2014, Goto et al 2014, Inaguma et al 2014, Cerami et al 2015, Noreau et al 2015, Gai et al 2016, Nair et al 2016, Bayram et al 2022, Rochdi et al 2022, Faheem et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Neuromuscular manifestations. Muscular hypotonia is usually present in early infancy resulting in motor delays. Distal and proximal muscular weakness is noticed during the first decade of life. Many affected individuals are never able to walk without assistance. Fine motor delays may also be present. 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.

Ocular manifestations. Bilateral cataracts are not necessarily congenital and can develop rapidly. The mean age at onset of cataracts is approximately 3.5 years [Krieger et al 2013, Goto et al 2014]. Cataracts typically require lens extraction in the first decade of life. Strabismus is present in at least half of individuals reported [Goto et al 2014].

Intellectual abilities vary from normal to severe intellectual disability.

Endocrine. 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. Additional typical clinical and radiographic skeletal findings include shortening of the 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 other clinical 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

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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MSS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

After counseling it is possible to clarify the genetic status of apparently asymptomatic at-risk sibs of an affected individual in order to initiate surveillance. Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Brain MRI or muscle biopsy to help identify features of MSS if the pathogenic variants in the family are not known.

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.

Mode of Inheritance

Marinesco-Sjögren syndrome (MSS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an MSS-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a SIL1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous SIL1 pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a SIL1 pathogenic variant, each sib of an affected individual has at conception 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.
• Intrafamilial variability is observed in MSS; manifestations of the disorder may vary among affected sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has MSS or is a carrier, offspring will be obligate heterozygotes (carriers) for an MSS-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an MSS-related pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SIL1 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with MSS, particularly if both partners are of the same ancestry. A SIL1 founder variant has been identified in the Finnish population (see Table 7).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

If biallelic 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

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.

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, an 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].

Mechanism of disease causation. Loss of function

Author Notes

Dr Anttonen is actively involved in clinical research regarding individuals with Marinesco-Sjögren syndrome (MSS) and would be happy to communicate with persons who have any questions regarding the diagnosis of MSS or other considerations.

Author History

Anna-Kaisa Anttonen, MD, PhD (2006-present)
Anna-Elina Lehesjoki, MD, PhD; University of Helsinki (2006-2019)

Revision History

• 3 October 2024 (sw) Comprehensive update posted live
• 10 January 2019 (ha) Comprehensive update posted live
• 7 September 2010 (me) Comprehensive update posted live
• 29 November 2006 (me) Review posted live
• 6 July 2006 (ael) Original submission

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