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<p>NGLY1 deficiency is a rare autosomal recessive genetic disorder caused by biallelic mutations of the human <i>NGLY1</i> gene. <i>NGLY1</i> encodes the cytosolic peptide:<i>N</i>-glycanase (PNGase; NGLY1 in mammals), which plays essential roles in cytosolic glycan degradation (non-lysosomal glycan degradation), the endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded proteins, and the complete activation of the transcription factor nuclear factor erythroid 2-like 1 (NEF2L1). NFE2L1 contributes to the regulation of the expression of proteasome subunits and oxidative stress responses. Patients with NGLY1 deficiency exhibit multisystemic clinical features, including global developmental delay, peripheral neuropathy, hypolacrima or alacrima, and the transient elevation of liver transaminases. To date, more than 100 individuals with NGLY1 deficiency and over 70 distinct pathogenic mutations in the <i>NGLY1</i> gene have been reported. There is currently no approved therapy for this disorder. Moreover, the underlying pathogenic mechanism, including the correlation between patients’ symptoms and mutant alleles, remains poorly understood. In this review, we summarize the most frequently reported <i>NGLY1</i> mutations and their associated clinical features. We also present an overview of the current therapeutic strategy for NGLY1 deficiency.</p>

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NGLY1 deficiency - clinical features and therapeutic strategy

  • 期刊论文

  • 发表日期：

    2025年7月29日

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  • Haruhiko Fujihira,
  • Hiroto Hirayama,
  • Tadashi Suzuki

摘要

NGLY1 deficiency is a rare autosomal recessive genetic disorder caused by biallelic mutations of the human NGLY1 gene. NGLY1 encodes the cytosolic peptide:N-glycanase (PNGase; NGLY1 in mammals), which plays essential roles in cytosolic glycan degradation (non-lysosomal glycan degradation), the endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded proteins, and the complete activation of the transcription factor nuclear factor erythroid 2-like 1 (NEF2L1). NFE2L1 contributes to the regulation of the expression of proteasome subunits and oxidative stress responses. Patients with NGLY1 deficiency exhibit multisystemic clinical features, including global developmental delay, peripheral neuropathy, hypolacrima or alacrima, and the transient elevation of liver transaminases. To date, more than 100 individuals with NGLY1 deficiency and over 70 distinct pathogenic mutations in the NGLY1 gene have been reported. There is currently no approved therapy for this disorder. Moreover, the underlying pathogenic mechanism, including the correlation between patients’ symptoms and mutant alleles, remains poorly understood. In this review, we summarize the most frequently reported NGLY1 mutations and their associated clinical features. We also present an overview of the current therapeutic strategy for NGLY1 deficiency.