NGLY1 – Congenital Disorder of Deglycosylation (CDDG)

NGLY1 deficiency, also known as congenital disorder of deglycosylation (CDDG), is a rare autosomal recessive disease caused by biallelic pathogenic variants in NGLY1, which encodes the cytosolic enzyme N-glycanase 1. Affected individuals present with global developmental delay, complex hyperkinetic movement disorder, hypo- or alacrima, and transiently elevated liver transaminases. Over 100 patients have been reported worldwide, confirming a consistent phenotype and inheritance pattern (PMID:36528660).

Genetic evidence for NGLY1–CDDG is definitive. To date, more than 100 patients from 74 families have been described, each with two loss-of-function or hypomorphic variants in NGLY1, including nonsense, frameshift, splice, and missense alleles (PMID:36528660). Reported variant spectrum includes c.1201A>T (p.Trp369Ter), a recurrent nonsense change observed homozygously in multiple unrelated probands (PMID:31326749).

Functional studies in patient fibroblasts and cell-based models demonstrate absent N-glycanase activity, accumulation of misfolded glycoprotein substrates, and loss of enzyme protein (PMID:25900930). Induced pluripotent stem cell (iPSC)–derived midbrain organoids recapitulate impaired neuronal development and reduced GABAergic signaling in NGLY1-deficient cells (PMID:36875753). In vivo, Ngly1–/– rodents exhibit motor deficits that are partially rescued by AAV-mediated NGLY1 gene replacement, supporting a loss-of-function mechanism and therapeutic potential for gene therapy (PMID:39137042).

The clinical spectrum has broadened through prospective phenotyping of 12 individuals, revealing additional features such as optic atrophy, joint hypermobility, and delayed skeletal maturation, alongside the core tetrad of developmental delay, movement disorder, hypolacrima, and transaminitis (PMID:27388694). Biochemical studies have also uncovered novel laboratory biomarkers, including elevated plasma methionine and S-adenosyl metabolites in individual patients (PMID:31497478).

Therapeutic exploration has included high-throughput screening for endo-β-N-acetylglucosaminidase (ENGase) inhibitors, identifying proton pump inhibitors as lead compounds, and small-molecule modulators of proteostasis. These efforts, alongside emerging gene replacement strategies, underscore the translational impact of mechanistic insights.

Key Take-Home

NGLY1–CDDG is a clinically definable autosomal recessive disorder with definitive gene-disease validity, a recognizable neurodevelopmental and systemic phenotype, and mounting experimental evidence guiding diagnostic biomarkers and potential therapies.

References

• Orphanet Journal of Rare Diseases • 2022 • NGLY1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the NGLY1 Registry. PMID:36528660
• Genetics in Medicine • 2017 • Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation. PMID:27388694
• JIMD Reports • 2019 • Transiently elevated plasma methionine, S-adenosylmethionine and S-adenosylhomocysteine: Unreported laboratory findings in a patient with NGLY1 deficiency, a congenital disorder of deglycosylation. PMID:31497478
• Glycobiology • 2015 • A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts. PMID:25900930
• Stem Cell Research • 2019 • An induced pluripotent stem cell line (TRNDi010-C) from a patient carrying a homozygous p.R401X mutation in the NGLY1 gene. PMID:31326749
• JCI Insight • 2024 • Systemic gene therapy corrects the neurological phenotype in a mouse model of NGLY1 deficiency. PMID:39137042

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