Marinesco-Sjögren syndrome (ORPHA:559)
A rare autosomal recessive disorder characterized by cerebellar ataxia, early-onset bilateral cataracts, chronic myopathy; additional features are delayed motor development and variable intellectual disability, hypergonadotrophic hypogonadism and delayed puberty, and short stature.
Epidemiology
Prevalence is not known, most likely in the 1-9/1,000,000 range. The estimated worldwide carrier frequency is 1:700, and in Finland it is 1:96. Disease onset occurs in infancy.
Clinical description
Hypotonia is usually present in early infancy, and muscle weakness is noticed during the first decade. Truncal ataxia, dysdiadochokinesia, nystagmus and dysarthria appear later. Cataracts can develop rapidly. Less constant features are skeletal deformities, somatic growth delay, and hypergonadotropic hypogonadism. Developmental milestones are often delayed and cognition varies from normal to severe intellectual disability. Cerebellar atrophy is observed on magnetic resonance imaging in all patients. Serum creatine kinase levels are usually only slightly or moderately elevated. Electromyography shows myopathic features. Electron microscopy of a muscle biopsy typically shows vacuolar myopathy and characteristic perinuclear membrane-like structures.
Etiology
Marinesco-Sjögren syndrome is caused by biallelic pathogenic variants in the SIL1 gene. Most of pathogenic variants are missense, but frameshift, nonsense and splice site variants have also been reported. SIL1 (nucleotide exchange factor SIL1) is present in the endoplasmic reticulum and plays a role as a co-chaperon in protein translocation into the endoplasmic reticulum, protein folding, control of degradation of misfolded proteins and response to cell stress. As a consequence, mutations in SIL1 lead to disturbance in proper folding of proteins and subsequently cell destruction.
Diagnostic methods
Diagnosis is based on typical clinical findings and/or biallelic pathogenic variants in the SIL1 gene. Ophthalmologic examination should be performed to detect cataract. Magnetic resonance imaging allows investigation of cerebellar atrophy particularly involving the vermis. Electron microscopy shows findings specific to Marinesco-Sjögren syndrome in muscle biopsy, while light microscopy does not.
Differential diagnosis
Differential diagnosis includes congenital cataracts-facial dysmorphism-neuropathy syndrome, congenital muscular dystrophy with cataracts and intellectual disability due to INPP5K gene variant, autosomal recessive spastic paraplegia type 46, autosomal recessive cerebellar ataxia with late-onset spasticity, ADan amyloidosis and dysequilibrium syndrome.
Antenatal diagnosis
Preimplantation or prenatal diagnosis are possible where the pathogenic variants have previously been identified in the index case and the parents.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant). The risk of recurrence of having an affected child is 25% at each pregnancy.
Management and treatment
Treatment is symptomatic. Cataracts often require surgical removal to preserve vision. Hormonal replacement therapy may be needed if hypogonadism is present. Physical and occupational therapy are crucial.
Prognosis
Patients can survive to old age, with varying disability.

                            Last update: 
                            December 2023


                            - Expert reviewer(s): 
                            Dr Dídac CASAS-ALBA | ITHACA* - Pr Francesc PALAU | ITHACA*


                                * European Reference Network