SNOMEDCT: 80734006; ORPHA: 559; DO: 0080195;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q31.2 | Marinesco-Sjogren syndrome | 248800 | Autosomal recessive | 3 | SIL1 | 608005 |
A number sign (#) is used with this entry because Marinesco-Sjogren syndrome (MSS) is caused by homozygous or compound heterozygous mutation in the SIL1 gene (608005) on chromosome 5q31.
Marinesco-Sjogren syndrome (MSS) is an autosomal recessive disorder characterized primarily by congenital cataracts, cerebellar ataxia, progressive muscle weakness due to myopathy, and delayed psychomotor development. Other features include short stature, hypergonadotropic hypogonadism, and skeletal deformities due to muscle weakness. MSS is genetically distinct from congenital cataracts, facial dysmorphism, and neuropathy (CCFDN; 604168), which is caused by mutation in the CTDP1 gene (604927) on chromosome 18q23, although the 2 disorders share some overlapping features, including congenital cataracts, delayed psychomotor development, and ataxia. The major distinguishing features are the presence of peripheral neuropathy, facial dysmorphism, and microcornea in CCFDN (Lagier-Tourenne et al., 2003).
Cerebellar ataxia, congenital cataracts, and retarded somatic and mental maturation are the cardinal features of MSS. Alter et al. (1962) suggested the designation 'hereditary oligophrenic cerebellolental degeneration.' Garland and Moorhouse (1953) published a striking pedigree. In a boy almost 5 years old, Todorov (1965) found the brain lesions limited almost exclusively to the cerebellum, which showed massive cortical atrophy. Many of the Purkinje cells that remained were vacuolated or binucleated.
Skre and Berg (1977) observed 10 persons with Marinesco-Sjogren syndrome in 2 kindreds, 9 of whom also had hypogonadism. The observations of Wertelecki (1986) also suggested that hypergonadotropic hypogonadism is a pleiotropic manifestation of the MSS gene.
In an inbred triracial (Indian, black, white) isolate in southwestern Alabama, Wertelecki (1986) found hypergonadotropic hypogonadism as a frequent feature among the many cases observed. In the same inbred group, Superneau et al. (1987) found progressive muscular weakness, hypotonia and atrophy to be among the cardinal signs. Most of the 17 patients studied had elevated serum creatine kinase (CK) levels and muscle biopsies showed myopathic changes. Conspicuous myopathy was present in 2 young children, indicating that myopathy is an early sign.
Walker et al. (1985) suggested that MSS may be a lysosomal storage disorder. In 4 patients from 2 different families and ethnic groups, they found, by electron microscopy, numerous enlarged lysosomes containing whorled lamellar or amorphous inclusion bodies.
Komiyama et al. (1989) reported that 3 of 4 adult patients in 2 families became 'nonambulant' because of slowly progressive muscular weakness rather than cerebellar ataxia. Other clinical features in these 4 patients were typical of MSS: bilateral cataracts from infancy, mental retardation, severe cerebellar atrophy, multiple skeletal abnormalities (pigeon chest, kyphoscoliosis, pes planovalgus), and hypergonadotropic hypogonadism. Electromyography showed a myopathic pattern, and serum creatine kinase was mildly elevated. Muscle biopsy showed chronic dystrophic changes. Tachi et al. (1991) described the histologic changes in muscle in an affected 2-year-old girl.
Zimmer et al. (1992) described the light- and electron-microscopic findings in skeletal muscle and conjunctiva of 6 related patients. Extensive neurogenic atrophy with conspicuous groups of atrophic muscle fibers was the most prominent feature in skeletal muscle of 4 patients. Conjunctival biopsies demonstrated a marked increase in the number of lysosomes in fibroblasts. Sasaki et al. (1996) described light- and electron-microscopic findings in the skeletal muscle of an 11-year-old boy. Electron microscopy demonstrated autophagic vacuoles with myeloid bodies and also a unique dense membranous structure associated with the nucleus which appeared not to be derived from the nuclear membrane. The authors suggested that it may be derived from the dense sarcoplasmic reticulum because of its thickness in electron density.
Farah et al. (1997) found MSS in 2 brothers in a consanguineous Bedouin family in Kuwait. The brothers were in their twenties. Both had abnormally short lateral 3 metatarsals, a feature not present in other healthy members of the family. Both showed features of hypergonadotropic hypogonadism.
Lagier-Tourenne et al. (2003) reported 2 consanguineous families, of Turkish and Norwegian origin, respectively, with MSS. The sister and brother in the Turkish family were referred to a neural pediatric clinic for failure to thrive, reduced head circumference, psychomotor delay, hypotonia, and a pronounced ataxic gait and limb ataxia. Disease progression was characterized by the occurrence of bilateral cataracts operated on at 4.5 and 6.5 years of age, respectively, and of skeletal deformities secondary to severe hypotonia and muscle weakness. MRI of the brain showed isolated marked cerebellar atrophy predominantly affecting the vermis. Muscle biopsy in each case showed myopathic changes.
Slavotinek et al. (2005) reported the case of a 5-year-old male with cataracts, ataxia, progressive cerebellar atrophy, developmental delay, seizures, hypotonia, and sensorimotor neuropathy consistent with the diagnosis of MSS. He also had mild craniofacial dysmorphism consisting of hypertrichosis and synophrys, deep-set eyes with epicanthic folds, flat philtrum, high palate, short thumbs, and wide sandal gap between the first and second toes.
In 4 members of 2 Finnish families, Herva et al. (1987) described a cerebrooculomuscular syndrome that the authors considered to be distinct from MSS. All patients had infantile hypotonia as the presenting sign. At school age, ataxia, cataract, and mental retardation became evident. CT scan showed cerebellar atrophy. Muscle biopsy showed myopathic changes with vacuolar degeneration and marked adipose tissue proliferation. Electron microscopy showed myelin bodies and autophagic vacuoles. These patients were later reported by Anttonen et al. (2005) to have MSS (Anttonen, 2006).
Anttonen et al. (2005) summarized the clinical features of typical MSS. Cerebellar ataxia due to cerebellar atrophy with Purkinje and granule cell loss is a hallmark of MSS. The myopathy is characterized by marked muscle replacement with fat and connective tissue, variation in fiber size, atrophic and necrotic myofibers, rimmed vacuoles, and autophagic vacuoles with membranous whorls on electron microscopy. Other cardinal features include bilateral cataracts, hypergonadotropic hypogonadism, and mild to severe mental retardation. Skeletal abnormalities, short stature, dysarthria, strabismus, and nystagmus are frequent findings.
Hasegawa et al. (2014) reported a 14-month-old Japanese boy with MSS. He had mild global developmental delay, nystagmus, cerebellar atrophy, and low serum IgG and IgA in the absence of opportunistic or recurrent infections. Whole-exome sequencing identified a homozygous truncating mutation in the SIL1 gene (608005.0008). Studies of patient-derived lymphoblastoid cells showed markedly decreased SIL1 expression as well as increased phosphorylation of EIF2A (609234), indicating increased ER stress, which Hasegawa et al. (2014) postulated may have hampered proper assembly of immunoglobulins in the ER. The patient was part of a cohort of 9 individuals with neurodegenerative features and hypogammaglobulinemia who underwent whole-exome sequencing. The report illustrated that whole-exome sequencing can lead to unpredictable molecular diagnoses and unexpected clinical features.
By homozygosity mapping in 2 large consanguineous families with MSS, 1 of Turkish and 1 of Norwegian origin, Lagier-Tourenne et al. (2003) localized the MSS locus to chromosome 5q31. A maximum lod score of 2.9 for the Turkish pedigree and 5.6 for the Norwegian pedigree at theta = 0.0 was obtained for linkage with the D5S1995-D5S436 haplotype spanning a 9.3-cM interval.
The transmission pattern of MSS in the families reported by Anttonen et al. (2005) was consistent with autosomal recessive inheritance.
In a Finnish family, Anttonen et al. (2005) confirmed linkage of the disease phenotype to 5q31; meiotic and historical recombinations defined a 3.52-Mb region with a shared haplotype in Finnish individuals with MSS. Further studies narrowed the region to 1.98 Mb, which excluded the gene SAR1B, also called SARA2 (607690), which had been suggested as a candidate. Anttonen et al. (2005) selected genes from the 1.98-Mb region for sequencing on the basis of tissue expression or predicted function. They identified a homozygous 4-nucleotide duplication, 506_509dupAAGA, in exon 6 of the SIL1 gene (608005.0001) in all Finnish individuals with MSS. Three of the Finnish patients had previously been reported by Herva et al. (1987) (Anttonen, 2006). Two Swedish individuals with MSS and a Finnish paternal ancestor were compound heterozygous with respect to the 506_509dupAAGA mutation and a donor splice site mutation in intron 6 (608005.0003). In all, 4 disease-associated, predicted loss-of-function mutations were found in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5 (138120). These data, together with a similar spatial and temporal patterns of tissue expression of SIL1 and HSPA5, suggested that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjogren syndrome.
Senderek et al. (2005) likewise used homozygosity mapping in 3 small consanguineous families with typical MSS to narrow a critical linkage region on 5q31 and identified 9 distinct mutations in SIL1 in individuals with Marinesco-Sjogren syndrome. Genetic heterogeneity in MSS was demonstrated by their failure to observe SIL1 mutations in 4 other individuals with typical MSS. No mutations were detected in 5 patients presenting with nonclassic MSS without myopathy but presenting with rarely described features such as peripheral neuropathy, microcornea, optic atrophy, and cerebral white matter changes. Senderek et al. (2005) defined Marinesco-Sjogren syndrome as a disease of endoplasmic reticulum dysfunction and suggested that this organelle has a role in multisystem disorders.
Aguglia et al. (2000) reported 2 Italian brothers who had MSS and chylomicron retention disease (CMRD; 246700). In these patients, Jones et al. (2003) identified a mutation in the SAR1B gene (607690.0006), responsible for CMRD, and Annesi et al. (2007) identified a mutation in the SIL1 gene (608005.0004), responsible for MSS. The findings indicated that the patients had 2 distinct diseases due to mutations in 2 different genes, rather than defects in a single gene leading to both disorders.
In affected members of 5 families with Marinesco-Sjogren syndrome. Anttonen et al. (2008) identified 4 novel homozygous mutations in the SIL1 gene (see, e.g., 608005.0007 and 608005.0008). All had the classic features of cerebellar atrophy and ataxia, cataracts, mental retardation, and some form of myopathy though severity varied somewhat. In SIL1-negative patients with a similar phenotype, Anttonen et al. (2008) excluded mutations in the HSPA5 (138120), HYOU1 (601746), and AARS (601065) genes.
In 3 Japanese sibs with Marinesco-Sjogren syndrome, Takahata et al. (2010) identified compound heterozygosity for 2 deletions in the SIL1 gene: a 5-bp deletion (598delGAAGA; 608005.0009) and a 58-kb deletion (608005.0010), both in exon 6. Each unaffected parent was heterozygous for 1 of the deletions. The 58-kb deletion was not detected by the standard PCR sequencing protocol and was only found after array comparative genomic hybridization and quantitative PCR analysis. Takahata et al. (2010) suggested that some MSS patients in whom mutations are not found should be screened for larger deletions in the SIL1 gene. All 3 patients had cataracts, ataxia, hypotonia, myopathy, spasticity, mental retardation, and skeletal deformities.
Anheim et al. (2010) found that MSS was the fourth most common form of autosomal recessive cerebellar ataxia in a cohort of 102 patients from Alsace, France. Of 57 patients in whom a molecular diagnosis could be determined, 3 were affected by MSS. FRDA (229300) was the most common diagnosis, found in 36 of 57 patients, AOA2 (606002) was the second most common diagnosis, found in 7 patients, and ataxia-telangiectasia (AT; 208900) was the third most common diagnosis, found in 4 patients. Ataxia-oculomotor apraxia-1 (AOA1; 208920) was found in 3 patients.
Superneau et al. (1985) pointed to a description of this syndrome reported in the Hungarian medical literature in 1904.
Chudley (2003) provided a biographic sketch of Georges Marinesco (1863-1938).
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