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.
Neurology. 2014 Apr 8;82(14):1254-60. doi: 10.1212/WNL.0000000000000295. Epub 2014 Mar 7.
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.
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.
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.
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.
研究先天性肌无力-胱氨酸尿症（HCS）和孤立性 PREPL 缺乏症的神经肌肉症状的遗传和生理基础，及其对治疗的反应。
我们进行了分子遗传学、组织化学、免疫印迹和超微结构研究，研究了孤立性 PREPL 缺乏症患者的体外神经肌肉传递，并评估了吡啶斯的明对该患者和 3 例 HCS 患者的疗效。
HCS 是由 SLC3A1 和 PREPL 基因的隐性缺失引起的。HCS 的主要临床特征是 A 型胱氨酸尿症、生长激素缺乏、肌无力、上睑下垂和喂养问题。孤立性 PREPL 缺乏症的先证者自出生以来即有肌无力症状，阳性的依酚氯铵试验，但无胱氨酸尿症。她和 3 例 HCS 患者中的 1 例在婴儿期对吡啶斯的明短暂反应。先证者携带 PREPL 的父系无义突变和涉及 PREPL 和 SLC3A1 的母系缺失；因此，PREPL 缺乏决定了表型。我们在患者的肌肉和终板中未检测到 PREPL 的表达。电生理学研究显示，终板电位的量子含量减少，微小终板电位的振幅降低，而终板乙酰胆碱受体缺乏或终板几何形状无改变。
孤立性 PREPL 缺乏症是一种新的单基因疾病，可引起先天性肌无力综合征，具有前突触和后突触特征以及生长激素缺乏症。PREPL 缺乏症伴或不伴胱氨酸尿症的肌无力症状可能在婴儿期对吡啶斯的明有反应。我们将肌无力归因于 PREPL 与衔接蛋白 1 的相互作用缺失。
