The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy
The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy
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SPTLC2 中的变异 p.(Arg183Trp) 导致迟发性遗传性感觉神经病
DOI：
10.1007/s12017-015-8379-1
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发表时间：
2015
影响因子：
3.5
通讯作者：
E. Ylikallio
中科院分区：
文献类型：
--
作者：
S. Suriyanarayanan;M. Auranen;J. Toppila;A. Paetau;Maria Shcherbii;E. Palin;Yu Wei;Tarja Lohioja;B. Schlotter‐Weigel;U. Schön;A. Abicht;B. Rautenstrauss;H. Tyynismaa;M. Walter;T. Hornemann;E. Ylikallio
遗传性感觉和自主神经病 1 (HSAN1) 是一种常染色体显性遗传疾病，可由编码丝氨酸棕榈酰辅酶 A 转移酶亚基的 SPTLC1 或 SPTLC2 变异引起。疾病变异会改变酶的底物特异性，并导致神经毒性 1-脱氧鞘脂的积累。我们描述了两个具有常染色体显性 HSAN1C 的家族，该家族是由 SPTLC2 中的新变体 c.547C>T，p.(Arg183Trp) 引起的。该变体改变了保守氨基酸，并且在公共变体数据库中未发现。所有患者均出现相对轻微的进行性远端感觉障碍，多于 50 岁后发病。小纤维较早受到影响，导致定量感觉测试异常。腓肠活检显示严重的慢性轴突神经病变，有髓鞘轴突部分全部丧失，非髓鞘纤维数量相对保留，无再生迹象。 PGP9.5 标记的皮肤活检显示疾病早期缺乏表皮内神经末梢。运动表现在病程后期出现，但没有自主神经受累的证据。患者血清1-脱氧鞘脂水平升高，而变异蛋白在体外产生的1-脱氧鞘脂含量升高，这证明了该变异体的致病性。我们的结果扩展了 HSAN1C 的遗传谱，并提供了有关临床特征的更多细节。所有患有轻度迟发型感觉为主的小纤维或大纤维神经病的患者均应考虑进行 SPTLC2 测序。
Hereditary sensory and autonomic neuropathy 1 (HSAN1) is an autosomal dominant disorder that can be caused by variants in SPTLC1 or SPTLC2, encoding subunits of serine palmitoyl-CoA transferase. Disease variants alter the enzyme’s substrate specificity and lead to accumulation of neurotoxic 1-deoxysphingolipids. We describe two families with autosomal dominant HSAN1C caused by a new variant in SPTLC2, c.547C>T, p.(Arg183Trp). The variant changed a conserved amino acid and was not found in public variant databases. All patients had a relatively mild progressive distal sensory impairment, with onset after age 50. Small fibers were affected early, leading to abnormalities on quantitative sensory testing. Sural biopsy revealed a severe chronic axonal neuropathy with subtotal loss of myelinated axons, relatively preserved number of non-myelinated fibers and no signs for regeneration. Skin biopsy with PGP9.5 labeling showed lack of intraepidermal nerve endings early in the disease. Motor manifestations developed later in the disease course, but there was no evidence of autonomic involvement. Patients had elevated serum 1-deoxysphingolipids, and the variant protein produced elevated amounts of 1-deoxysphingolipids in vitro, which proved the pathogenicity of the variant. Our results expand the genetic spectrum of HSAN1C and provide further detail about the clinical characteristics. Sequencing of SPTLC2 should be considered in all patients presenting with mild late-onset sensory-predominant small or large fiber neuropathy.
影响因子：
15.9
作者：
Garofalo, Kevin;Penno, Anke;Eichler, Florian S.
通讯作者：
Eichler, Florian S.