PREPL – Congenital Myasthenic Syndrome-22

Congenital myasthenic syndrome-22 (CMS22) is a rare autosomal recessive neuromuscular transmission disorder caused by biallelic variants in PREPL. To date, ten unrelated patients have been reported with loss-of-function variants and large deletions ([PMID:32707643]). Affected individuals present with fatigable weakness, neonatal hypotonia, ptosis, feeding difficulties, and growth hormone deficiency.

Genetic analyses across five families have revealed a spectrum of pathogenic variants including nonsense, splice-site, frameshift, and contiguous gene deletions. In one pedigree, a proband carried compound heterozygous variants c.1528C>T (p.Arg510Ter) and c.2094G>T (p.Lys698Asn), the latter proven by minigene assay to induce exon 14 skipping, while a sibling was homozygous for c.1528C>T due to maternal uniparental disomy ([PMID:32707643]). Additional isolated PREPL deficiency cases identified nine novel alleles in five patients via exome sequencing and MLPA ([PMID:28726805]).

Segregation analysis in the index family confirmed co-segregation of biallelic PREPL variants in two affected siblings and heterozygosity in parents, with one additional affected relative identified ([PMID:32707643]).

Clinical features overlap include fatigable weakness (HP:0003473), neonatal hypotonia (HP:0001319), ptosis (HP:0000508), and growth hormone deficiency (HP:0000824) ([PMID:28726805]). Some patients exhibit transient improvement with pyridostigmine, supporting a neuromuscular transmission defect ([PMID:24610330]).

Functional studies corroborate pathogenicity: splicing assays for c.2094G>T confirm aberrant exon skipping ([PMID:32707643]); immunoblot of lymphocytes shows absent PREPL protein in affected subjects ([PMID:28726805]); in vitro electrophysiology reveals reduced quantal content and miniature endplate potential amplitude without receptor deficiency ([PMID:24610330]); and Prepl knockout mice exhibit impaired mitochondrial complex activities and disrupted gene expression, linking PREPL loss to neuromuscular and metabolic phenotypes ([PMID:34888501]).

Collectively, strong genetic and moderate experimental evidence support a strong gene–disease relationship. PREPL variant analysis and functional assays are recommended for patients with congenital myasthenic features to guide diagnosis and inform timely therapeutic decisions.

References

• Genes • 2020 • A Family Case of Congenital Myasthenic Syndrome-22 Induced by Different Combinations of Molecular Causes in Siblings. PMID:32707643
• Genetics in Medicine • 2018 • PREPL deficiency: delineation of the phenotype and development of a functional blood assay. PMID:28726805
• Neurology • 2014 • PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome. PMID:24610330
• iScience • 2021 • Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function. PMID:34888501

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