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

Régal, Luc; Mårtensson, Emma LU ; Maystadt, Isabelle; Voermans, Nicol; Lederer, Damien; Burlina, Alberto; Juan Fita, María Jesús; Hoogeboom, A. Jeannette M.; Olsson Engman, Mia and Hollemans, Tess, et al. (2018) In Genetics in Medicine 20(1). p.109-118
Abstract

PurposePREPL 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.MethodsClinical features of new subjects with PREPL deficiency were recorded. The presence of PREPL in lymphocytes and its reactivity with an... (More)

PurposePREPL 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.MethodsClinical 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.ResultsFive 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.ConclusionPREPL 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.

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published
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keywords
blood assay, hypotonia-cystinuria syndrome, neonatal hypotonia8Prader-Willi syndrome, PREPL
in
Genetics in Medicine
volume
20
issue
1
pages
10 pages
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:85040465071
  • pmid: 28726805
ISSN
1098-3600
DOI
10.1038/gim.2017.74
language
English
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yes
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d89c9c9a-a02a-4229-8ec8-eaf587a364ed
date added to LUP
2018-02-05 12:23:43
date last changed
2018-02-06 03:00:09
@article{d89c9c9a-a02a-4229-8ec8-eaf587a364ed,
  abstract     = {<p>PurposePREPL 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.MethodsClinical 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.ResultsFive 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.ConclusionPREPL 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.</p>},
  author       = {Régal, Luc and Mårtensson, Emma and Maystadt, Isabelle and Voermans, Nicol and Lederer, Damien and Burlina, Alberto and Juan Fita, María Jesús and Hoogeboom, A. Jeannette M. and Olsson Engman, Mia and Hollemans, Tess and Schouten, Meyke and Meulemans, Sandra and Jonson, Tord and François, Inge and Gil Ortega, David and Kamsteeg, Erik Jan and Creemers, John W.M.},
  issn         = {1098-3600},
  keyword      = {blood assay,hypotonia-cystinuria syndrome,neonatal hypotonia8Prader-Willi syndrome,PREPL},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {109--118},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Genetics in Medicine},
  title        = {PREPL deficiency : Delineation of the phenotype and development of a functional blood assay},
  url          = {http://dx.doi.org/10.1038/gim.2017.74},
  volume       = {20},
  year         = {2018},
}