Marinesco-Sjögren Syndrome

Rare autosomal recessive multisystem disorder characterized by a classic tetrad:

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%

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

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

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