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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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