A Family Case of Congenital Myasthenic Syndrome-22 Induced by Different Combinations of Molecular Causes in Siblings

Щагина, О. А.; Bessonova, L. A.; Bychkov, Igor; Beskorovainaya, T. S.; Poliakov, Aleksander

doi:10.3390/genes11070821

Cited by 4 publications

(4 citation statements)

References 14 publications

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“…PREPL- CMS without pathogenic variants SLC3A1 has been reported in 11 patients since 2014 [ 33 , 351 , 370 , 371 , 372 , 373 , 374 , 375 , 376 ]. Similarly, PREPL- CMS with SLC3A1 deletion, the diagnosis of which is HCS, has been reported in 7 patients since 2014 [ 33 , 351 ].…”

Section: Thirty-five Genes In 14 Groups Of Cmsmentioning

confidence: 99%

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

Ohno

Ohkawara

Shen

et al. 2023

IJMS

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Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.

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Section: Thirty-five Genes In 14 Groups Of Cmsmentioning

confidence: 99%

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

Ohno

Ohkawara

Shen

et al. 2023

IJMS

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“…Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a rare recessive disorder caused by mutations in the prolyl endopeptidase-like (PREPL) gene (1)(2)(3)(4)(5)(6). Patients experience severe neonatal hypotonia, eyelid ptosis, feeding problems and growth hormone deficiency.…”

Section: Introductionmentioning

confidence: 99%

“…During childhood, the hypotonia spontaneously improves and patients develop hyperphagia and rapid weight gain (1,2,4,(6)(7)(8)(9)(10)(11)(12)(13). Approximately half of the patients experience learning difficulties and have an average IQ of 70 (3). Previous reports have mostly documented CMS22 patient harboring partial or complete loss of PREPL alone or together with flanking genes (1,2,4,(6)(7)(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

“…Previous reports have mostly documented CMS22 patient harboring partial or complete loss of PREPL alone or together with flanking genes (1,2,4,(6)(7)(8)(9)(10)(11)(12)(13). In addition, a small number of point mutations in the PREPL gene have been identified, leading to a frameshift or premature stop codon (1)(2)(3)(4)(5)(6). Recently, a patient with a missense mutation in PREPL was reported but not functionally characterized (14).…”

Section: Introductionmentioning

confidence: 99%

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Missense mutations in CMS22 patients reveal that PREPL has both enzymatic and non-enzymatic functions

Monnens,

Theodoropoulou,

Rosier

et al. 2023

Preprint

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Congenital myasthenic syndrome-22 (CMS22) is a rare genetic disorder caused by mutations in the prolyl endopeptidase-like (PREPL) gene. Since previous reports only described patients with deletions and nonsense mutations inPREPL, nothing is known about the effect of missense mutations in the pathology of CMS22. In this study, we have characterized missense mutations inPREPLin three CMS22 patients, all with hallmark phenotypes. Biochemical evaluation revealed that these missense mutations do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria. Structural analysis shows that the mutations affect regions most likely involved in intra-protein or protein-protein interactions. Indeed, binding to a selected group of known interactors was differentially reduced for the three mutants. The importance of non-hydrolytic functions of PREPL was investigated in catalytically inactive PREPL p.Ser559Ala cell lines which showed that hydrolytic activity of PREPL is needed for normal mitochondrial function but not for regulating AP1-mediated transport in the trans-Golgi network. In conclusion, these studies show that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense mutations that do not necessarily result in a loss of hydrolytic activity of PREPL.Graphical abstract

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Maternal Uniparental Isodisomy of Chromosome 2 Leading to Homozygous Variants in SPR and ZNF142: A Case Report and Review of the UPD2 Literature

Kelkar,

DiMaio,

et al. 2024

Glob Med Genet

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We report a 4-year-old girl with neurodevelopmental abnormalities who has maternal uniparental isodisomy of chromosome 2 leading to homozygosity for a likely pathogenic variant in SPR, and a variant of uncertain significance in ZNF142. Biallelic pathogenic variants in SPR lead to sepiapterin reductase deficiency (SRD), a dopa-responsive dystonia. Pathogenic variants in ZNF142 are associated with an autosomal recessive neurodevelopmental disorder characterized by impaired speech and hyperkinetic movements, which has significant clinical overlap with SRD. Our patient showed dramatic improvement in motor skills after treatment with levodopa. We also reviewed 67 published reports of uniparental disomy of chromosome 2 (UPD2) associated with various clinical outcomes. These include autosomal recessive disorders associated with loci on chromosome 2, infants with UPD2 whose gestations were associated with confined placental mosaicism for trisomy 2 leading to intrauterine growth restriction with good postnatal catchup growth, and normal phenotypes in children and adults with an incidental finding of either maternal or paternal UPD2. These latter reports provide support for the conclusion that genes located on chromosome 2 are not subject to imprinting. We also explore the mechanisms giving rise to UPD2.

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A Family Case of Congenital Myasthenic Syndrome-22 Induced by Different Combinations of Molecular Causes in Siblings

Cited by 4 publications

References 14 publications

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

Missense mutations in CMS22 patients reveal that PREPL has both enzymatic and non-enzymatic functions

Maternal Uniparental Isodisomy of Chromosome 2 Leading to Homozygous Variants in SPR and ZNF142: A Case Report and Review of the UPD2 Literature

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