Marinesco-Sjögren Syndrome -CEW

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====== Marinesco-Sjögren Syndrome ======

Rare autosomal recessive multisystem disorder characterized by a classic tetrad: 
  - Cerebellar ataxia
  - Early-onset cataracts
  - Intellectual disability
  - Progressive myopathy.

====Main Features====

  * **Cerebellar ataxia** — present in >90% of patients, with cerebellar atrophy seen on MRI in 100%
  * **Cataracts** — present in 95–100%; mean onset ~3.5 years; typically requires lens extraction in the first decade of life
  * **Intellectual disability** — present in >90%; ranges from mild to severe, though normal intelligence has been reported
  * **Myopathy** — myopathic changes on EMG or muscle biopsy in >90%; muscle weakness, hypotonia, and atrophy are common*
  * **Hypotonia** — present in 95–100%

====Eye Findings====

  * **Cataracts** — the hallmark ocular feature (95–100%); develops in early childhood and may be absent in infants, which can delay diagnosis
  * **Strabismus** — present in 60–80% of affected individuals
  * **Nystagmus** — observed in ~50%, likely related to cerebellar dysfunction
  * **Optic atrophy** — rare; reported in a review of 75 patients
  * **Glaucoma** — rare
  * **Microphthalmia** — rare
  * **Retinal degeneration** — rare
  * **Iris coloboma** — reported as a novel finding in some patients

====Other Findings====

  * **Hypergonadotropic hypogonadism** — 50–70%; delayed or absent puberty; no associated congenital genital anomalies described
  * **Short stature** — 50–70%; microcephaly occasionally reported
  * **Skeletal abnormalities** — ~50%; includes scoliosis, shortened metacarpals/metatarsals/phalanges, coxa valga, pes planovalgus, and pectus carinatum
  * **Dysarthria** — reported in ~45% of patients
  * **Pyramidal tract signs** — modestly constant feature
  * **Dental abnormalities** — reported in some patients
  * **Life span** — appears to be near normal despite significant disability

====Etiology====

  * **Gene:** SIL1 (chromosome 5q31)
  * **Protein:** SIL1 encodes BIP-associated protein (BAP), a 461-amino acid endoplasmic reticulum (ER) resident co-chaperone
  * **Function:** BAP acts as a nucleotide exchange factor for the ER chaperone BiP (HSPA5/GRP78), promoting ATP–ADP exchange essential for protein folding and transport in the ER
  * **Pathophysiology:** Loss-of-function mutations lead to severely reduced or absent BAP protein, resulting in impaired ER protein processing and ER stress-induced cell damage
  * **Inheritance:** Autosomal recessive
  * **Genetic heterogeneity:** SIL1 mutations account for ~60% of patients with the classic triad; patients without SIL1 mutations are clinically indistinguishable, suggesting additional causative genes exist
  * **Founder effect:** In Japan, the SIL1 c.936dupG (p.Leu313fs) mutation was found on 43/48 chromosomes tested, with haplotype analysis suggesting a founder effect

====References====

  - [[https://pubmed.ncbi.nlm.nih.gov/24176978|Krieger M, Roos A, Stendel C, et al. SIL1 Mutations and Clinical Spectrum in Patients With Marinesco-Sjogren Syndrome. Brain. 2013]]
  - [[https://pubmed.ncbi.nlm.nih.gov/17296802|Fogel BL, Perlman S. Clinical Features and Molecular Genetics of Autosomal Recessive Cerebellar Ataxias. Lancet Neurol. 2007]]
  - [[https://medlineplus.gov/genetics/condition/marinesco-sjogren-syndrome|National Library of Medicine (MedlinePlus). Marinesco-Sjögren syndrome. 2015]]
  - [[https://www.ncbi.nlm.nih.gov/books/NBK1192|Anttonen AK. Marinesco-Sjögren Syndrome. GeneReviews. 2024]]
  - [[https://pubmed.ncbi.nlm.nih.gov/23062754|Horvers M, Anttonen AK, Lehesjoki AE, et al. Marinesco-Sjögren Syndrome Due to SIL1 Mutations With a Comment on the Clinical Phenotype. Eur J Paediatr Neurol. 2013]]
  - [[https://pubmed.ncbi.nlm.nih.gov/15523624|Slavotinek A, Goldman J, Weisiger K, et al. Marinesco-Sjögren syndrome in a male with mild dysmorphism. Am J Med Genet A. 2005]]
  - [[https://pubmed.ncbi.nlm.nih.gov/24033328|Ezgu F, Krejci P, Li S, et al. Phenotype-genotype correlations in patients with Marinesco-Sjögren syndrome. Clin Genet. 2014]]
  - [[https://pubmed.ncbi.nlm.nih.gov/24755310|Goto M, Okada M, Komaki H, et al. A Nationwide Survey on Marinesco-Sjögren Syndrome in Japan. Orphanet J Rare Dis. 2014]]
  - [[http://www.ncbi.nlm.nih.gov/books/NBK1192/?report=reader|Gene Reviews]]


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syndrome