Alternative name(s) : Myasthenic syndrome, congenitzl, 22; CMS22, PREPL deficiency
Gene_locus : 1
Mutation : 15
Comment
(from OMIM) Congenital myasthenic syndrome-22 (CMS22) is caused by homozygous or compound heterozygous mutation in the PREPL gene on chromosome 2p21. Homozygous deletion of both PREPL and the neighboring gene SLC3A1 causes hypotonia-cystinuria syndrome. Regal et al. (2014) reported a female infant who presented with marked neonatal hypotonia, eyelid ptosis, tented upper lip, and feeding difficulties. She was treated with a feeding tube and showed a favorable response to the acetylcholinesterase (AChE) inhibitor pyridostigmine, from which she was weaned at age 12 months without deterioration, suggesting spontaneous improvement with age. She walked at 17 months, but had a waddling gait and used a walker. She also had growth hormone deficiency but did not have cystinuria. Language development and brain imaging were normal. Regal et al. (2018) reported 5 new patients with CMS22. All manifested severe neonatal hypotonia, neonatal feeding problems, and nasal dysarthria. All had high-arched palates and narrow bitemporal diameter. Patients with CMS22 walked at a median age of 23 months and had residual signs of neuromuscular involvement in adulthood, including facial weakness, nasal dysarthria, and paretic neck flexion. Most subjects had ptosis and facial weakness as well as fluctuating weakness. Most also had hypergonadotropic hypogonadism. The cognitive profile of patients with either CMS22 or the hypotonia-cystinuria syndrome ranged from mild intellectual disability to normal intelligence. The median IQ was 70. Growth hormone deficiency was detected in 4 of 5 subjects, with an age of onset ranging from 20 months to 11 years. Regal et al. (2018) remarked that in all of the 5 patients they described with CMS22. They noted that patients with CMS22 have ptosis, which is absent in patients with Prader-Willi syndrome. In a girl with CMS22, Regal et al. (2014) identified a heterozygous 33.6-kb deletion of chromosome 2p21 including exons 5 to 10 of the SLC3A1 gene (104614) and exons 9 to 14 of the PREPL gene inherited from the unaffected mother, and a heterozygous frameshift mutation in the PREPL gene inherited from the unaffected father. These findings indicated that the patient retained a functional SLC3A1 allele, and that the phenotype was determined by homozygous mutation in PREPL. Immunoblot analysis of patient muscle showed absence of PREPL in muscle fibers and at the endplates in the neuromuscular junction. Patient endplates showed normal AChR and AChE expression, as well as abundant synaptic vesicles. However, one endplate showed a degenerating nerve terminal, and another had autophagic vacuoles in the junctional sarcoplasm and an abandoned postsynaptic region. Microelectrode studies showed reduced MEPP and MEPC amplitudes and decreased quantal content with decreased levels of ACh in the synaptic vesicles. Additional changes noted at the endplate pointed to a defect in the late stages of exocytosis. Regal et al. (2014) hypothesized that PREPL deficiency may affect function of the clathrin-associated adaptor protein-1 (see AP1M1, 603535) and filling of synaptic vesicles. Regal et al. (2018) described 5 previously unreported patients with isolated PREPL deficiency (CMS22) and detected novel PREPL mutations in each. Missense variants in CMS22 patients reveal that PREPL has both enzymatic and non-enzymatic functions
Title : Missense variants in CMS22 patients reveal that PREPL has both enzymatic and non-enzymatic functions - Monnens_2024_JCI.Insight__e179276 |
Author(s) : Monnens Y , Theodoropoulou A , Rosier K , Bhalla K , Mahy A , Vanhoutte R , Meulemans S , Cavani E , Antanasijevic A , Lemmens I , Lee JA , Spellicy CJ , Schroer RJ , Maselli RA , Laverty CG , Agostinis P , Pagliarini DJ , Verhelst S , Marcaida MJ , Rochtus A , Dal Peraro M , Creemers JW |
Ref : JCI Insight , : , 2024 |
Abstract : |
PubMedSearch : Monnens_2024_JCI.Insight__e179276 |
PubMedID: 39078710 |
Gene_locus related to this paper: human-PREPL |
Title : Similar metabolic pathways are affected in both Congenital Myasthenic Syndrome-22 and Prader-Willi Syndrome - Bhalla_2024_Biochim.Biophys.Acta.Mol.Basis.Dis__167175 |
Author(s) : Bhalla K , Rosier K , Monnens Y , Meulemans S , Vervoort E , Thorrez L , Agostinis P , Meier DT , Rochtus A , Resnick JL , Creemers JWM |
Ref : Biochimica & Biophysica Acta Mol Basis Dis , :167175 , 2024 |
Abstract : |
PubMedSearch : Bhalla_2024_Biochim.Biophys.Acta.Mol.Basis.Dis__167175 |
PubMedID: 38626828 |
Title : Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review - Ohno_2023_Int.J.Mol.Sci_24_ |
Author(s) : Ohno K , Ohkawara B , Shen XM , Selcen D , Engel AG |
Ref : Int J Mol Sci , 24 : , 2023 |
Abstract : |
PubMedSearch : Ohno_2023_Int.J.Mol.Sci_24_ |
PubMedID: 36835142 |
Gene_locus related to this paper: human-PREPL |
Title : Prolyl Endopeptidase-like Deficiency Associated with Growth Hormone Deficiency - Sayol-Torres_2023_J.Clin.Res.Pediatr.Endocrinol_15_205 |
Author(s) : Sayol-Torres L , Valenzuela MI , Tomasini R , Fernandez-Alvarez P , Clemente M , Yeste D |
Ref : J Clin Res Pediatr Endocrinol , 15 :205 , 2023 |
Abstract : |
PubMedSearch : Sayol-Torres_2023_J.Clin.Res.Pediatr.Endocrinol_15_205 |
PubMedID: 34693706 |
Gene_locus related to this paper: human-PREPL |
Title : Hypotonia-cystinuria 2p21 deletion syndrome: Intrafamilial variability of clinical expression - Towheed_2021_Ann.Clin.Transl.Neurol_8_2199 |
Author(s) : Towheed A , Hietanen CL , Kamath VG , Singh LN , Ho A , Engelstad K , Cornett K , Montes J , De Vivo D |
Ref : Ann Clin Transl Neurol , 8 :2199 , 2021 |
Abstract : |
PubMedSearch : Towheed_2021_Ann.Clin.Transl.Neurol_8_2199 |
PubMedID: 34612606 |
Gene_locus related to this paper: human-PREPL |
Title : Congenital Myasthenic Syndrome From a Single Center: Phenotypic and Genotypic features - Prior_2021_J.Child.Neurol_36_610 |
Author(s) : Prior DE , Ghosh PS |
Ref : Journal of Child Neurology , 36 :610 , 2021 |
Abstract : |
PubMedSearch : Prior_2021_J.Child.Neurol_36_610 |
PubMedID: 33471587 |
Gene_locus related to this paper: human-PREPL |
Title : PREPL Deficiency: A Homozygous Splice Site PREPL Mutation in a Patient With Congenital Myasthenic Syndrome and Absence of Ovaries and Hypoplasia of Uterus - Yang_2020_Front.Genet_11_198 |
Author(s) : Yang Q , Hua R , Qian J , Yi S , Shen F , Zhang Q , Li M , Luo J , Fan X |
Ref : Front Genet , 11 :198 , 2020 |
Abstract : |
PubMedSearch : Yang_2020_Front.Genet_11_198 |
PubMedID: 32218803 |
Gene_locus related to this paper: human-PREPL |
Title : First maternal uniparental disomy for chromosome 2 with PREPL novel frameshift mutation of congenital myasthenic syndrome 22 in an infant - Zhang_2020_Mol.Genet.Genomic.Med_8_e1144 |
Author(s) : Zhang P , Wu B , Lu Y , Ni Q , Liu R , Zhou W , Wang H |
Ref : Mol Genet Genomic Med , 8 :e1144 , 2020 |
Abstract : |
PubMedSearch : Zhang_2020_Mol.Genet.Genomic.Med_8_e1144 |
PubMedID: 31985178 |
Gene_locus related to this paper: human-PREPL |
Title : Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders - Kim_2020_J.Clin.Med_9_3724 |
Author(s) : Kim MJ , Yum MS , Seo GH , Lee Y , Jang HN , Ko TS , Lee BH |
Ref : J Clin Med , 9 : , 2020 |
Abstract : |
PubMedSearch : Kim_2020_J.Clin.Med_9_3724 |
PubMedID: 33233562 |
Gene_locus related to this paper: human-PREPL |
Title : A Family Case of Congenital Myasthenic Syndrome-22 Induced by Different Combinations of Molecular Causes in Siblings - Shchagina_2020_Genes.(Basel)_11_821 |
Author(s) : Shchagina O , Bessonova L , Bychkov I , Beskorovainaya T , Poliakov A |
Ref : Genes (Basel) , 11 :821 , 2020 |
Abstract : |
PubMedSearch : Shchagina_2020_Genes.(Basel)_11_821 |
PubMedID: 32707643 |
Gene_locus related to this paper: human-PREPL |
Title : Isolated PREPL deficiency associated with congenital myasthenic syndrome-22 - |
Author(s) : Laugwitz L , Redler S , Buchert R , Sturm M , Zeile I , Schara U , Wieczorek D , Haack T , Distelmaier F |
Ref : Klin Padiatr , 230 :281 , 2018 |
PubMedID: 29913539 |
Gene_locus related to this paper: human-PREPL |
Title : PREPL deficiency: delineation of the phenotype and development of a functional blood assay - Regal_2018_Genet.Med_20_109 |
Author(s) : Regal L , Martensson E , Maystadt I , Voermans N , Lederer D , Burlina A , Juan Fita MJ , Hoogeboom AJM , Olsson Engman M , Hollemans T , Schouten M , Meulemans S , Jonson T , Francois I , Gil Ortega D , Kamsteeg EJ , Creemers JWM |
Ref : Genet Med , 20 :109 , 2018 |
Abstract : |
PubMedSearch : Regal_2018_Genet.Med_20_109 |
PubMedID: 28726805 |
Gene_locus related to this paper: human-PREPL |
Title : The second point mutation in PREPL: a case report and literature review - Silva_2018_J.Hum.Genet_63_677 |
Author(s) : Silva S , Miyake N , Tapia C , Matsumoto N |
Ref : J Hum Genet , 63 :677 , 2018 |
Abstract : |
PubMedSearch : Silva_2018_J.Hum.Genet_63_677 |
PubMedID: 29483676 |
Gene_locus related to this paper: human-PREPL |
Title : PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome - Regal_2014_Neurology_82_1254 |
Author(s) : Regal L , Shen XM , Selcen D , Verhille C , Meulemans S , Creemers JW , Engel AG |
Ref : Neurology , 82 :1254 , 2014 |
Abstract : |
PubMedSearch : Regal_2014_Neurology_82_1254 |
PubMedID: 24610330 |
Gene_locus related to this paper: human-PREPL |
Title : Deletion of PREPl causes growth impairment and hypotonia in mice - Lone_2014_PLoS.One_9_e89160 |
Author(s) : Lone AM , Leidl M , McFedries AK , Horner JW , Creemers J , Saghatelian A |
Ref : PLoS ONE , 9 :e89160 , 2014 |
Abstract : |
PubMedSearch : Lone_2014_PLoS.One_9_e89160 |
PubMedID: 24586561 |
Gene_locus related to this paper: human-PREPL |
Title : Further delineation of genotype-phenotype correlation in homozygous 2p21 deletion syndromes: first description of patients without cystinuria - Bartholdi_2013_Am.J.Med.Genet.A_161a_1853 |
Author(s) : Bartholdi D , Asadollahi R , Oneda B , Schmitt-Mechelke T , Tonella P , Baumer A , Rauch A |
Ref : American Journal of Medicine Genet A , 161a :1853 , 2013 |
Abstract : |
PubMedSearch : Bartholdi_2013_Am.J.Med.Genet.A_161a_1853 |
PubMedID: 23794250 |
Gene_locus related to this paper: human-PREPL |