The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment.
The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment.
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DOI：
10.1111/nan.12842
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发表时间：
2022-12
影响因子：
5
通讯作者：
Nolano, Maria
中科院分区：
文献类型：
--
作者：
Fiorillo, Chiara;Capodivento, Giovanna;Geroldi, Alessandro;Tozza, Stefano;Moroni, Isabella;Mohassel, Payam;Cataldi, Matteo;Campana, Chiara;Morando, Simone;Panicucci, Chiara;Pedemonte, Marina;Brolatti, Noemi;Siliquini, Sabrina;Traverso, Monica;Baratto, Serena;Debellis, Doriana;Magri, Stefania;Prada, Valeria;Bellone, Emilia;Salpietro, Vincenzo;Donkervoort, Sandra;Gable, Kenneth;Gupta, Sita D.;Dunn, Teresa M.;Bonnemann, Carsten G.;Taroni, Franco;Bruno, Claudio;Schenone, Angelo;Mandich, Paola;Nobbio, Lucilla;Nolano, Maria
SPTLC1相关疾病是一种与鞘脂稳态紊乱相关的晚发性感觉自主神经病变，可通过补充丝氨酸棕榈酰辅酶a转移酶（SPT）底物l -丝氨酸来改善。最近，一种青少年形式的运动神经元疾病与SPTLC1变异有关。影响SPTLC1的p.S331残基的变异导致不同的表型，其致病基础尚未确定。本研究旨在确定SPTLC1 p.S331变异的神经病理和生化后果，并测试该特定基因型对l -丝氨酸的反应。我们报告了两个不相关的儿童携带不同的p.S331 SPTLC1变异的临床和神经生理学特征。通过腓肠神经和皮肤神经支配的分析来观察神经病理学。为了阐明p.S331变异的生化后果，我们对血清和皮肤成纤维细胞进行了鞘脂组学分析。我们还测试了补充l -丝氨酸对p.S331突变患者皮肤成纤维细胞的影响。在这两名患者中，我们发现了一种具有普遍进行性运动神经元疾病的早发表型。神经病理学显示感觉和自主神经系统严重受损。鞘脂组学分析显示，神经毒性脱氧鞘脂与过量的SPT酶标准产物共存。在患者成纤维细胞中补充L -丝氨酸减少了毒性1 -脱氧鞘脂的产生，但进一步增加了鞘脂的过量产生。我们的研究结果表明，p.S331 SPTLC1变异导致了感觉和运动神经病变特征的重叠表型，从而提出了SPTLC1相关疾病谱系的连续体。这些患者补充L -丝氨酸可能是有害的。SPTLC1谱系障碍的范围从成人发病的感觉神经病变到儿童发病的肌萎缩侧索硬化症，它们与神经鞘脂体内平衡紊乱有关，这是可以治疗的。SPLTC1基因S331密码子突变与单独的综合征表型有关。该研究提供了临床、神经病理和生化证据，支持S331突变实际上导致重叠表型，连接感觉神经病变和运动神经元疾病，并提醒治疗选择。
SPTLC1‐related disorder is a late onset sensory‐autonomic neuropathy associated with perturbed sphingolipid homeostasis which can be improved by supplementation with the serine palmitoyl‐CoA transferase (SPT) substrate, l‐serine. Recently, a juvenile form of motor neuron disease has been linked to SPTLC1 variants. Variants affecting the p.S331 residue of SPTLC1 cause a distinct phenotype, whose pathogenic basis has not been established. This study aims to define the neuropathological and biochemical consequences of the SPTLC1 p.S331 variant, and test response to l‐serine in this specific genotype. We report clinical and neurophysiological characterisation of two unrelated children carrying distinct p.S331 SPTLC1 variants. The neuropathology was investigated by analysis of sural nerve and skin innervation. To clarify the biochemical consequences of the p.S331 variant, we performed sphingolipidomic profiling of serum and skin fibroblasts. We also tested the effect of l‐serine supplementation in skin fibroblasts of patients with p.S331 mutations. In both patients, we recognised an early onset phenotype with prevalent progressive motor neuron disease. Neuropathology showed severe damage to the sensory and autonomic systems. Sphingolipidomic analysis showed the coexistence of neurotoxic deoxy‐sphingolipids with an excess of canonical products of the SPT enzyme. l‐serine supplementation in patient fibroblasts reduced production of toxic 1‐deoxysphingolipids but further increased the overproduction of sphingolipids. Our findings suggest that p.S331 SPTLC1 variants lead to an overlap phenotype combining features of sensory and motor neuropathies, thus proposing a continuum in the spectrum of SPTLC1‐related disorders. l‐serine supplementation in these patients may be detrimental. SPTLC1 spectrum disorder ranges from adult onset sensory neuropathy to childhood onset ALS and they are related to perturbed homeostasis of sphingolipids which can betreatable. Mutation of the S331 codon of SPLTC1 gene were related to a separate syndromic phenotype. This study provides clinical, neuropathological and biochemical evidences supporting the fact that S331 mutations actually result in an overlapping phenotype which bridges sensory neuropathy and motor neuron disease and alerts on treatment options.
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影响因子：
3.9
作者：
Rotthier, Annelies;Penno, Anke;Janssens, Katrien
通讯作者：
Janssens, Katrien
影响因子：
82.9
作者：
Mohassel, Payam;Donkervoort, Sandra;Lone, Museer A.;Nalls, Matthew;Gable, Kenneth;Gupta, Sita D.;Foley, A. Reghan;Hu, Ying;Saute, Jonas Alex Morales;Moreira, Ana Lucila;Kok, Fernando;Introna, Alessandro;Logroscino, Giancarlo;Grunseich, Christopher;Nickolls, Alec R.;Pourshafie, Naemeh;Neuhaus, Sarah B.;Saade, Dimah;Gangfuss, Andrea;Koelbel, Heike;Piccus, Zoe;Le Pichon, Claire E.;Fiorillo, Chiara;Ly, Cindy V.;Topf, Ana;Brady, Lauren;Specht, Sabine;Zidell, Aliza;Pedro, Helio;Mittelmann, Eric;Thomas, Florian P.;Chao, Katherine R.;Konersman, Chamindra G.;Cho, Megan T.;Brandt, Tracy;Straub, Volker;Connolly, Anne M.;Schara, Ulrike;Roos, Andreas;Tarnopolsky, Mark;Hoke, Ahmet;Brown, Robert H.;Lee, Chia-Hsueh;Hornemann, Thorsten;Dunn, Teresa M.;Bonnemann, Carsten G.
通讯作者：
Bonnemann, Carsten G.
影响因子：
3.5
作者：
McCampbell, A;Truong, D;Brown, RH
通讯作者：
Brown, RH
影响因子：
3.4
作者：
Fridman, Vera;Oaklander, Anne Louise;Eichler, Florian S.
通讯作者：
Eichler, Florian S.
影响因子：
9.9
作者：
Fridman, Vera;Suriyanarayanan, Saranya;Eichler, Florian
通讯作者：
Eichler, Florian