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April 08, 2014; 82 (14) Article

PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome

Luc Régal, Xin-Ming Shen, Duygu Selcen, Chantal Verhille, Sandra Meulemans, John W.M. Creemers, Andrew G. Engel
First published March 7, 2014, DOI: https://doi.org/10.1212/WNL.0000000000000295
Luc Régal
From the Center of Human Genetics (L.R., J.W.M.C., S.M.), Laboratory of Biochemical Neuroendocrinology, KU Leuven; Department of Pediatrics and Pediatric Metabolic Disorders (C.V.), University Hospital Leuven, Belgium; and Department of Neurology (X.-M.S., D.S., A.G.E.), Mayo Clinic, Rochester, MN.
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Xin-Ming Shen
From the Center of Human Genetics (L.R., J.W.M.C., S.M.), Laboratory of Biochemical Neuroendocrinology, KU Leuven; Department of Pediatrics and Pediatric Metabolic Disorders (C.V.), University Hospital Leuven, Belgium; and Department of Neurology (X.-M.S., D.S., A.G.E.), Mayo Clinic, Rochester, MN.
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Duygu Selcen
From the Center of Human Genetics (L.R., J.W.M.C., S.M.), Laboratory of Biochemical Neuroendocrinology, KU Leuven; Department of Pediatrics and Pediatric Metabolic Disorders (C.V.), University Hospital Leuven, Belgium; and Department of Neurology (X.-M.S., D.S., A.G.E.), Mayo Clinic, Rochester, MN.
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Chantal Verhille
From the Center of Human Genetics (L.R., J.W.M.C., S.M.), Laboratory of Biochemical Neuroendocrinology, KU Leuven; Department of Pediatrics and Pediatric Metabolic Disorders (C.V.), University Hospital Leuven, Belgium; and Department of Neurology (X.-M.S., D.S., A.G.E.), Mayo Clinic, Rochester, MN.
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Sandra Meulemans
From the Center of Human Genetics (L.R., J.W.M.C., S.M.), Laboratory of Biochemical Neuroendocrinology, KU Leuven; Department of Pediatrics and Pediatric Metabolic Disorders (C.V.), University Hospital Leuven, Belgium; and Department of Neurology (X.-M.S., D.S., A.G.E.), Mayo Clinic, Rochester, MN.
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John W.M. Creemers
From the Center of Human Genetics (L.R., J.W.M.C., S.M.), Laboratory of Biochemical Neuroendocrinology, KU Leuven; Department of Pediatrics and Pediatric Metabolic Disorders (C.V.), University Hospital Leuven, Belgium; and Department of Neurology (X.-M.S., D.S., A.G.E.), Mayo Clinic, Rochester, MN.
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Andrew G. Engel
From the Center of Human Genetics (L.R., J.W.M.C., S.M.), Laboratory of Biochemical Neuroendocrinology, KU Leuven; Department of Pediatrics and Pediatric Metabolic Disorders (C.V.), University Hospital Leuven, Belgium; and Department of Neurology (X.-M.S., D.S., A.G.E.), Mayo Clinic, Rochester, MN.
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Citation
PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome
Luc Régal, Xin-Ming Shen, Duygu Selcen, Chantal Verhille, Sandra Meulemans, John W.M. Creemers, Andrew G. Engel
Neurology Apr 2014, 82 (14) 1254-1260; DOI: 10.1212/WNL.0000000000000295

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Abstract

Objective: To investigate the genetic and physiologic basis of the neuromuscular symptoms of hypotonia-cystinuria syndrome (HCS) and isolated PREPL deficiency, and their response to therapy.

Methods: We performed molecular genetic, histochemical, immunoblot, and ultrastructural studies, investigated neuromuscular transmission in vitro in a patient with isolated PREPL deficiency, and evaluated the effect of pyridostigmine in this patient and in 3 patients with the HCS.

Results: HCS is caused by recessive deletions involving the SLC3A1 and PREPL genes. The major clinical features of HCS are type A cystinuria, growth hormone deficiency, muscle weakness, ptosis, and feeding problems. The proband with isolated PREPL deficiency had myasthenic symptoms since birth and a positive edrophonium test but no cystinuria. She and 1 of 3 patients with HCS responded transiently to pyridostigmine during infancy. The proband harbors a paternally inherited nonsense mutation in PREPL and a maternally inherited deletion involving both PREPL and SLC3A1; therefore, the PREPL deficiency determines the phenotype. We detected no PREPL expression in the patient's muscle and endplates. Electrophysiology studies revealed decreased quantal content of the endplate potential and reduced amplitude of the miniature endplate potential without endplate acetylcholine receptor deficiency or altered endplate geometry.

Conclusion: Isolated PREPL deficiency is a novel monogenic disorder that causes a congenital myasthenic syndrome with pre- and postsynaptic features and growth hormone deficiency. The myasthenic symptoms in PREPL deficiency with or without cystinuria may respond to pyridostigmine in early life. We attribute the myasthenia to abrogated interaction of PREPL with adaptor protein 1.

Glossary

ACh=
acetylcholine;
AChR=
acetylcholine receptor;
AP-1=
adaptor protein 1;
bp=
base pair;
cDNA=
complementary DNA;
EP=
endplate;
EPP=
endplate potential;
HCS=
hypotonia-cystinuria syndrome;
IGF=
insulin-like growth factor;
MEPC=
miniature endplate current;
MEPP=
miniature endplate potential;
OMIM=
Online Mendelian Inheritance in Man;
SNARE=
soluble N-ethylmaleimide-sensitive factor atachment protein receptor

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • ↵* These authors contributed equally to this work.

  • Supplemental data at Neurology.org

  • Received October 15, 2013.
  • Accepted in final form December 26, 2013.
  • © 2014 American Academy of Neurology
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