18º Congresso Brasileiro de Neurologia Infantil

Dados do Trabalho



Apresentação do caso

Female, 2nd child of healthy, non-consanguineous parents. Born at term with uneventful delivery. At one month old, parents noticed feeding difficulties and weight gain was inadequate requiring the placement of a nasogastric tube. Muscular hypotonia, delayed motor development in addition to a nasal voice was noted. Diagnostic work-up including laboratory screening for metabolic diseases, brain and spine MRI, echocardiogram, ophthalmological evaluation was unremarkable. Whole exome sequencing revealed a homozygous splicing mutation (c.970 -1 G>A) in the PREPL gene (NM_0006036.4).


The prolyl endopeptidase like gene (PREPL; MIM 609557, NM_006036.4) is located in 2p21, and encodes PREPL protein which is a cytoplasmic serine hydrolase structurally belonging to an oligopeptidase family. Prolyl peptidases have the capacity to participate in cellular regulatory processes, including cell division, apoptosis, cell differentiation, as their substrates are involved in regulating different signaling pathways. PREPL function is to redistribute clathrin-associated adaptor protein complex 1 (AP- 1) from the cell membrane into the cytoplasm. AP-1 is a soluble cytoplasmic protein with highest expression in the central nervous system, muscle and kidney. The trafficking of the vesicular Acetylcholine (Ach) transporter is mediated by AP-1 with PREPL redistributing AP-1 from membranes into cytoplasm. PREPL deficiency causes a reduction in the filling of ACh synaptic vesicles.
A therapeutic intervention with pyridostigmine improves myasthenic symptoms if the patient is treated early in life.
Congenital myasthenic syndrome-22 (CMS22) is an autosomal recessive disorder caused by isolated PREPL deficiency. However, different recessive contiguous gene deletion syndromes involving PREPL and a variable combination of SLC3A1 (hypotonia–cystinuria syndrome), CAMKMT (atypical hypotonia– cystinuria syndrome), and PPM1B (2p21 deletion syndrome) have been described. Patients with isolated PREPL deficiency often experience severe hypotonia during the neonatal period, muscular and facial weakness, nasal dysarthria, feeding problems, ptosis, failure to thrive, short stature, growth hormone deficiency, hypergonadotropic hypogonadism.

Comentários finais

As the course of PREPL deficiency is particular in the spontaneous improvement of the severe neonatal hypotonia and several manifestations can be treated with pyridostigmine, an early molecular diagnosis becomes crucial.

Referências (se houver)

Yang Q, Hua R, Qian J, Yi S, Shen F, Zhang Q, Li M, Yi S, Luo J, Fan X. PREPL Deficiency: A Homozygous Splice Site PREPL Mutation in a Patient With Congenital Myasthenic Syndrome and Absence of Ovaries and Hypoplasia of Uterus. Front Genet. 2020 Mar 11;11:198. doi: 10.3389/fgene.2020.00198. PMID: 32218803; PMCID: PMC7078161.

Régal L, Mårtensson 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, François I, Gil Ortega D, Kamsteeg EJ, Creemers JWM. PREPL deficiency: delineation of the phenotype and development of a functional blood assay. Genet Med. 2018 Jan;20(1):109-118. doi: 10.1038/gim.2017.74. Epub 2017 Jul 20. PMID: 28726805.

Laugwitz L, Redler S, Buchert R, Sturm M, Zeile I, Schara U, Wieczorek D, Haack T, Distelmaier F. Isolated PREPL deficiency associated with congenital myasthenic syndrome-22. Klin Padiatr. 2018 Sep;230(5):281-283. English. doi: 10.1055/a-0605-3659. Epub 2018 Jun 18. PMID: 29913539.

Müller JS, Mihaylova V, Abicht A, Lochmüller H. Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission. Expert Rev Mol Med. 2007 Aug 9;9(22):1-20. doi: 10.1017/S1462399407000427. PMID: 17686188.

Palavras Chave

congenital myasthenic syndrome, PREPL gene, splicing mutation, neonatal hypotonia, CMC22

Fonte de Fomento (se houver)

Declaração de conflito de interesses de TODOS os autores

Não há


Doenças neuromusculares


Hospital das Clínicas da Faculdade de Medicina da USP - HCFMUSP - São Paulo - Brasil


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