PREPL deficiency: delineation of the phenotype and development of a functional blood assay

• Published in: Genetics in medicine Vol. 20; no. 1; pp. 109 - 118
• Main Authors: Régal, Luc, Mårtensson, Emma, Maystadt, Isabelle, Voermans, Nicol, Lederer, Damien, Burlina, Alberto, Juan Fita, María Jesús, Hoogeboom, A. Jeannette M., Olsson Engman, Mia, Hollemans, Tess, Schouten, Meyke, Meulemans, Sandra, Jonson, Tord, François, Inge, Gil Ortega, David, Kamsteeg, Erik-Jan, Creemers, John W.M.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.01.2018; Nature Publishing Group US; Elsevier Limited
• Subjects: 692/699/1702; 692/700/139/1512; 692/700/1720/3186; Adolescent; Adult; Biomedical and Life Sciences; Biomedicine; blood assay; Child; Child, Preschool; Chromosome Aberrations; Clinical Medicine; Comparative Genomic Hybridization; Enzyme Activation; Facies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Human Genetics; Humans; hypotonia–cystinuria syndrome; Infant; Infant, Newborn; Klinisk medicin; Laboratory Medicine; Male; Medical and Health Sciences; Medicin och hälsovetenskap; neonatal hypotonia; original-research-article; Pediatrics; Pediatrik; Phenotype; Prader–Willi syndrome; PREPL; Prolyl Oligopeptidases; Serine Endopeptidases - deficiency; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Young Adult; PREPL; Prader–Willi syndrome; hypotonia–cystinuria syndrome; neonatal hypotonia; blood assay; neonatal hypotonia; Prader–Willi syndrome; PREPL
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/gim.2017.74

PREPL deficiency causes neonatal hypotonia, ptosis, neonatal feeding difficulties, childhood obesity, xerostomia, and growth hormone deficiency. 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. In isolated PREPL deficiency, previously described only once, the absence of cystinuria complicates the diagnosis. Therefore, we developed a PREPL blood assay and further delineated the phenotype. Clinical features of new subjects with PREPL deficiency were recorded. The presence of PREPL in lymphocytes and its reactivity with an activity-based probe were evaluated by western blot. Five subjects with isolated PREPL deficiency, three with hypotonia-cystinuria syndrome, and two with atypical hypotonia-cystinuria syndrome had nine novel alleles. Their IQs ranged from 64 to 112. Adult neuromuscular signs included ptosis, nasal dysarthria, facial weakness, and variable proximal and neck flexor weakness. Autonomic features are prevalent. PREPL protein and reactivity were absent in lymphocytes from subjects with PREPL deficiency, but normal in the clinically similar Prader–Willi syndrome. PREPL deficiency causes neuromuscular, autonomic, cognitive, endocrine, and dysmorphic clinical features. PREPL is not deficient in Prader–Willi syndrome. The novel blood test should facilitate the confirmation of PREPL deficiency.