Dataset Information

MR imaging features in Marinesco-Sjogren syndrome: severe cerebellar atrophy is not an obligatory finding.

ABSTRACT:

Background and purpose

Cerebellar atrophy is considered the most prominent neuroradiologic finding in Marinesco-Sjögren syndrome (MSS). Our purpose was to investigate this neuroradiologic feature in a series of patients with MSS.

Methods

Five patients with MSS (age range, 5-19 years) underwent native MR imaging of the brain. The findings were assessed with particular attention to the cerebellum and the supratentorial structures.

Results

Only two patients had slight cerebellar atrophy; the cerebellum was normal in size and configuration in the other patients. Additional supratentorial findings were present in some of the patients, with an apparently small anterior pituitary gland in two and the absence of the posterior pituitary bright spot in three of the patients.

Conclusion

Cerebellar atrophy is not an obligatory finding in MSS, and almost normal cranial MR imaging results are compatible with the diagnosis. Morphologic changes of the pituitary gland seem to be common in patients with MSS and are not associated with endocrine dysfunction.

SUBMITTER: Reinhold A

PROVIDER: S-EPMC7975805 | biostudies-literature | 2003 May

REPOSITORIES: biostudies-literature

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Publications

MR imaging features in Marinesco-Sjögren syndrome: severe cerebellar atrophy is not an obligatory finding.

Reinhold Anke A Scheer Ianina I Lehmann Rüdiger R Neumann Luitgard M LM Michael Theodor T Varon Raymonda R Von Moers Arpad A

AJNR. American journal of neuroradiology 20030501 5

<h4>Background and purpose</h4>Cerebellar atrophy is considered the most prominent neuroradiologic finding in Marinesco-Sjögren syndrome (MSS). Our purpose was to investigate this neuroradiologic feature in a series of patients with MSS.<h4>Methods</h4>Five patients with MSS (age range, 5-19 years) underwent native MR imaging of the brain. The findings were assessed with particular attention to the cerebellum and the supratentorial structures.<h4>Results</h4>Only two patients had slight cerebell ...[more]

PMID: 12748078

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Project description:Marinesco-Sjogren syndrome (MSS) is a rare multisystem pediatric disorder, caused by loss-of-function mutations in the gene encoding the endoplasmic reticulum cochaperone SIL1. SIL1 acts as a nucleotide exchange factor for BiP, which plays a central role in secretory protein folding. SIL1 mutant cells have reduced BiP-assisted protein folding, cannot fulfil their protein needs, and experience chronic activation of the unfolded protein response (UPR). Maladaptive UPR may explain the cerebellar and skeletal muscle degeneration responsible for the ataxia and muscle weakness typical of MSS. However, the cause of other more variable, clinical manifestations, such as mild to severe mental retardation, hypogonadism, short stature, and skeletal deformities, is less clear. To gain insights into the pathogenic mechanisms and/or adaptive responses to SIL1 loss, we carried out cell biological and proteomic investigations in skin fibroblasts derived from a young patient carrying the SIL1 R111X mutation. Despite fibroblasts not being overtly affected in MSS, we found morphological and biochemical changes indicative of UPR activation and altered cell metabolism. All the cell machineries involved in RNA splicing and translation were strongly downregulated, while protein degradation via lysosome-based structures was boosted, consistent with an attempt of the cell to reduce the workload of the endoplasmic reticulum and dispose of misfolded proteins. Cell metabolism was extensively affected as we observed a reduction in lipid synthesis, an increase in beta oxidation, and an enhancement of the tricarboxylic acid cycle, with upregulation of eight of its enzymes. Finally, the catabolic pathways of various amino acids, including valine, leucine, isoleucine, tryptophan, lysine, aspartate, and phenylalanine, were enhanced, while the biosynthetic pathways of arginine, serine, glycine, and cysteine were reduced. These results indicate that, in addition to UPR activation and increased protein degradation, MSS fibroblasts have profound metabolic alterations, which may help them cope with the absence of SIL1.

Project description:BackgroundMarinesco-Sjögren syndrome (MSS) is an autosomal recessive neuromuscular disorder that arises in early childhood and is characterized by congenital cataracts, myopathy associated with muscle weakness, and degeneration of Purkinje neurons leading to ataxia. About 60% of MSS patients have loss-of-function mutations in the SIL1 gene. Sil1 is an endoplasmic reticulum (ER) protein required for the release of ADP from the master chaperone Bip, which in turn will release the folded proteins. The expression of non-functional Sil1 leads to the accumulation of unfolded proteins in the ER and this triggers the unfolded protein response (UPR). A dysfunctional UPR could be a key element in the pathogenesis of MSS, although our knowledge of the molecular pathology of MSS is still incomplete.MethodsRNA-Seq transcriptomics was analysed using the String database and the Ingenuity Pathway Analysis platform. Fluorescence confocal microscopy was used to study the remodelling of the extracellular matrix (ECM). Transmission electron microscopy (TEM) was used to reveal the morphology of the ECM in vitro and in mouse tendon.ResultsOur transcriptomic analysis, performed on patient-derived fibroblasts, revealed 664 differentially expressed (DE) transcripts. Enrichment analysis of DE genes confirmed that the patient fibroblasts have a membrane trafficking issue. Furthermore, this analysis indicated that the extracellular space/ECM and the cell adhesion machinery, which together account for around 300 transcripts, could be affected in MSS. Functional assays showed that patient fibroblasts have a reduced capacity of ECM remodelling, reduced motility, and slower spreading during adhesion to Petri dishes. TEM micrographs of negative-stained ECM samples from these fibroblasts show differences of filaments in terms of morphology and size. Finally, structural analysis of the myotendinous junction of the soleus muscle and surrounding regions of the Achilles tendon revealed a disorganization of collagen fibres in the mouse model of MSS (woozy).ConclusionsECM alterations can affect the proper functioning of several organs, including those damaged in MSS such as the central nervous system, skeletal muscle, bone and lens. On this basis, we propose that aberrant ECM is a key pathological feature of MSS and may help explain most of its clinical manifestations.