2. Academic Validation
  3. PREPL deficiency: delineation of the phenotype and development of a functional blood assay

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.
Luc Régal 1 2,  Emma Mårtensson 3,  Isabelle Maystadt 4,  Nicol Voermans 5,  Damien Lederer 4,  Alberto Burlina 6,  María Jesús Juan Fita 7,  A Jeannette M Hoogeboom 8,  Mia Olsson Engman 9,  Tess Hollemans 2,  Meyke Schouten 10,  Sandra Meulemans 1,  Tord Jonson 3,  Inge François 11,  David Gil Ortega 7,  Erik-Jan Kamsteeg 10,  John W M Creemers 1
Affiliations

Affiliations

  • 1 Laboratory of Biochemical Neuroendocrinology, Department of Human Genetics, University of Leuven, Leuven, Belgium.
  • 2 Pediatric Neurology and Metabolism, Department of Pediatrics, UZ Brussel, Brussels, Belgium.
  • 3 Department of Clinical Genetics, Region Skåne and Lund University, Lund, Sweden.
  • 4 Centre de Génétique Humaine, Institut de Pathologie et Génétique, Charleroi, Belgium.
  • 5 Department of Neurology, RadboudUMC Nijmegen, Nijmegen, The Netherlands.
  • 6 Division of Inherited Metabolic Diseases, Department of Pediatrics, University Hospital Padova, Padova, Italy.
  • 7 Unidad de Metabolopatías, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
  • 8 Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • 9 Department of Pediatrics, Blekinge Hospital, Karlskrona, Sweden.
  • 10 Department of Clinical Genetics, RadboudUMC Nijmegen, Nijmegen, The Netherlands.
  • 11 Department of Pediatric Endocrinology, UZ Leuven, Leuven, Belgium.
PMID: 28726805 DOI: 10.1038/gim.2017.74
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 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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