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<p>Niemann-Pick disease type B (NPD-B) is a rare lysosomal storage disorder characterized by residual activity of acid sphingomyelinase (ASM). While functional inhibitors of ASM (FIASMAs) are widely prescribed as psychotropic medications, they may pose a particular risk to patients with NPD-B by further reducing the already impaired enzymatic function. Here, we report the case of a 20-year-old male with genetically confirmed NPD-B who experienced rapid clinical deterioration following the administration of zuclopenthixol, a drug not previously associated with FIASMA activity. Within 48 hours of treatment initiation, the patient developed profound lethargy and markedly elevated creatine kinase (CK) levels of up to 22,000 U/L, consistent with rhabdomyolysis. Symptoms resolved quickly after discontinuation of zuclopenthixol. In vitro experiments using a radioactive [<sup>1 4</sup> C]-sphingomyelin assay in Jurkat cells demonstrated that zuclopenthixol dose-dependently inhibited ASM activity by up to 71.5%. Zuclopenthixol had not previously been recognized as a FIASMA and might therefore have been considered a rational choice for treating patients with NPD-B. Our findings challenge this assumption by identifying zuclopenthixol as a potent inhibitor of ASM activity. This novel insight is of high clinical relevance, given the frequent use of antipsychotics in the management of neuropsychiatric symptoms in lysosomal storage disorders. We propose that zuclopenthixol and other potential FIASMAs be carefully re-evaluated for use in this vulnerable patient population.</p>

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Zuclopenthixol inhibits residual activity of acid sphingomyelinase in Niemann pick disease type B: a case report with in vitro validation

  • 期刊论文

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  • 发表日期：

    2026年4月9日

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  • Maximilian Schiller,
  • Katharina Marie Steiner,
  • Udo Bonnet,
  • Erich Gulbins,
  • Norbert Scherbaum

摘要

Niemann-Pick disease type B (NPD-B) is a rare lysosomal storage disorder characterized by residual activity of acid sphingomyelinase (ASM). While functional inhibitors of ASM (FIASMAs) are widely prescribed as psychotropic medications, they may pose a particular risk to patients with NPD-B by further reducing the already impaired enzymatic function. Here, we report the case of a 20-year-old male with genetically confirmed NPD-B who experienced rapid clinical deterioration following the administration of zuclopenthixol, a drug not previously associated with FIASMA activity. Within 48 hours of treatment initiation, the patient developed profound lethargy and markedly elevated creatine kinase (CK) levels of up to 22,000 U/L, consistent with rhabdomyolysis. Symptoms resolved quickly after discontinuation of zuclopenthixol. In vitro experiments using a radioactive [1 4 C]-sphingomyelin assay in Jurkat cells demonstrated that zuclopenthixol dose-dependently inhibited ASM activity by up to 71.5%. Zuclopenthixol had not previously been recognized as a FIASMA and might therefore have been considered a rational choice for treating patients with NPD-B. Our findings challenge this assumption by identifying zuclopenthixol as a potent inhibitor of ASM activity. This novel insight is of high clinical relevance, given the frequent use of antipsychotics in the management of neuropsychiatric symptoms in lysosomal storage disorders. We propose that zuclopenthixol and other potential FIASMAs be carefully re-evaluated for use in this vulnerable patient population.