Genotype-phenotype correlations in ocular manifestations of Marinesco–Sjögren syndrome: Case report and literature review

Bayram, Nurettin; Bayram, Ayşe Kaçar; Daimagüler, Hülya Sevcan; Dafsari, Hormos Salimi; Bamborschke, Daniel; Uyanık, Gökhan; Erdoğan, Murat; Özsaygılı, Cemal; Pangal, Emine; Yuvacı, İsa; Doğanay, Selim; Gümüş, Hakan; Per, Hüseyin; Jungbluth, Heinz; Çırak, Sebahattin

doi:10.1177/11206721211021291

Cited by 5 publications

(4 citation statements)

References 10 publications

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“…The elevated CK levels with a peak of 2900 IU/L are similar to reports of PME patients in the literature. While this does not automatically preclude the patient from having muscular dystrophy, the muscle biopsy showed only mild increase of mitochondria and there were no other phenotypic signs indicative of muscular dystrophy in this patient, e.g., ocular structural changes, progressive loss of muscle mass, or Gower's sign [7,33]. Indeed, while elevated CK levels may prompt further investigations on future clinical presentation, any CK elevation here was interpreted as likely arising from myoclonus.…”

Section: Studymentioning

confidence: 64%

“…We performed massively parallel sequencing with sequence alignment and variant calling as previously published [7,8]. We performed filtering for rare pathogenic variants below an allele frequency of <0.1% following recessive and dominant inheritance models.…”

Section: Molecular Genetic Investigationsmentioning

confidence: 99%

“…We performed filtering for rare pathogenic variants below an allele frequency of <0.1% following recessive and dominant inheritance models. In a first step, we filtered for dystonia-associated genes (GCH1, GCE, TH, SPR, ATP1A3, FTL, PRKRA, TUBB4A, BCAP31, COX20, KIF1C, SLC30A10, ANO3) [7,9,10].…”

Section: Molecular Genetic Investigationsmentioning

confidence: 99%

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Novel Genetic and Phenotypic Expansion in GOSR2-Related Progressive Myoclonus Epilepsy

Hentrich,

Parnes,

Lotze

et al. 2023

Genes

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Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the GOSR2 founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic–clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype–phenotype spectrum of GOSR2-related disorders and suggest that GOSR2 should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures.

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Section: Studymentioning

confidence: 64%

Section: Molecular Genetic Investigationsmentioning

confidence: 99%

See 1 more Smart Citation

Novel Genetic and Phenotypic Expansion in GOSR2-Related Progressive Myoclonus Epilepsy

Hentrich,

Parnes,

Lotze

et al. 2023

Genes

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“…The linear protein model was visualized with the IBS illustrator tool [53]. We conducted protein modeling on the missense variant in patient 3 in wildtype and mutant form with DynaMut2 to assess pathogenicity in patient mutations.…”

Section: Molecular Genetic Investigationsmentioning

confidence: 99%

Novel Genetic and Phenotypic Expansion in Ameliorated PUF60-Related Disorders

Baum,

Huang,

Vincent-Delorme

et al. 2024

IJMS

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Heterozygous variants in the Poly(U) Binding Splicing Factor 60kDa gene (PUF60) have been associated with Verheij syndrome, which has the key features of coloboma, short stature, skeletal abnormalities, developmental delay, palatal abnormalities, and congenital heart and kidney defects. Here, we report five novel patients from unrelated families with PUF60-related disorders exhibiting novel genetic and clinical findings with three truncating variants, one splice-site variant with likely reduced protein expression, and one missense variant. Protein modeling of the patient’s missense variant in the PUF60 AlphaFold structure revealed a loss of polar bonds to the surrounding residues. Neurodevelopmental disorders were present in all patients, with variability in speech, motor, cognitive, social-emotional and behavioral features. Novel phenotypic expansions included movement disorders as well as immunological findings with recurrent respiratory, urinary and ear infections, atopic diseases, and skin abnormalities. We discuss the role of PUF60 in immunity with and without infection based on recent organismic and cellular studies. As our five patients showed less-severe phenotypes than classical Verheij syndrome, particularly with the absence of key features such as coloboma or palatal abnormalities, we propose a reclassification as PUF60-related neurodevelopmental disorders with multi-system involvement. These findings will aid in the genetic counseling of patients and families.

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An update on autophagy disorders

Dafsari,

Martinelli,

Saffari

et al. 2024

J of Inher Metab Disea

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Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post‐mitotic tissues, congenital disorders of autophagy, due to monogenic defects in key autophagy genes, share a common “clinical signature” including neurodevelopmental, neurodegenerative, and neuromuscular features, as well as variable abnormalities of the eyes, skin, heart, bones, immune cells, and other organ systems, depending on the expression pattern and the specific function of the defective proteins. Since the clinical and genetic resolution of EPG5‐related Vici syndrome, the paradigmatic congenital disorder of autophagy, the widespread use of massively parallel sequencing has resulted in the identification of a growing number of autophagy‐associated disease genes, encoding members of the core autophagy machinery as well as related proteins. Recently identified monogenic disorders linking selective autophagy, vesicular trafficking, and other pathways have further expanded the molecular and phenotypical spectrum of congenital disorders of autophagy as a clinical disease spectrum. Moreover, significant advances in basic research have enhanced the understanding of the underlying pathophysiology as a basis for therapy development. Here, we review (i) autophagy in the context of other intracellular trafficking pathways; (ii) the main congenital disorders of autophagy and their typical clinico‐pathological signatures; and (iii) the recommended primary health surveillance in monogenic disorders of autophagy based on available evidence. We further discuss recently identified molecular mechanisms that inform the current understanding of autophagy in health and disease, as well as perspectives on future therapeutic approaches.

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Genotype-phenotype correlations in ocular manifestations of Marinesco–Sjögren syndrome: Case report and literature review

Cited by 5 publications

References 10 publications

Novel Genetic and Phenotypic Expansion in GOSR2-Related Progressive Myoclonus Epilepsy

Novel Genetic and Phenotypic Expansion in GOSR2-Related Progressive Myoclonus Epilepsy

Novel Genetic and Phenotypic Expansion in Ameliorated PUF60-Related Disorders

An update on autophagy disorders

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