RARE DISEASE
Alacrimia-choreoathetosis-liver dysfunction syndrome
Alacrimia-choreoathetosis-liver dysfunction syndrome
Alacrimia-choreoathetosis-liver dysfunction syndrome
Synonyms: NGLY1 deficiency, NGLY1-CDDG
Synonyms: NGLY1 deficiency, NGLY1-CDDG
Synonyms: NGLY1 deficiency, NGLY1-CDDG
Drug discovery
3
drugs
With orphan designations
Overview
Alacrimia-choreoathetosis-liver dysfunction syndrome (ALCDS) is a rare autosomal recessive disorder characterized by global developmental delay, hypotonia, choreoathetosis, hypo-/alacrimia, and liver dysfunction with elevated transaminases and hepatocyte storage abnormalities. Associated features include seizures, peripheral neuropathy, intellectual disability, and ocular anomalies such as optic atrophy. Brain imaging often reveals cerebral/cerebellar atrophy and myelination defects [1][2][16].
Burden
High morbidity due to severe developmental regression, motor disability, and treatment-resistant seizures [1][2].
Liver involvement contributes to life-threatening complications requiring frequent monitoring [3][16].
Caregiver burden is substantial given profound intellectual impairment and lifelong dependency [9][16].
Therapies
Symptomatic management: Antiepileptics for seizures, lubricants for alacrimia, hepatoprotective agents for liver dysfunction [2][16].
Supportive care: Multidisciplinary approach including physical/occupational therapy and nutritional support [2][9].
Experimental therapies: NGLY1 enzyme replacement/modulator therapies in early clinical trials (Phase 1/2) [11].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare skin diseases
Research Papers
66 drug discovery papers about Alacrimia-choreoathetosis-liver dysfunction syndrome, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
66 drug discovery papers about Alacrimia-choreoathetosis-liver dysfunction syndrome, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-08-14 | Comparative proteomics of HepG2 cells reveals NGLY1 as an important regulator of ferroptosis resistance and iron uptake.
NGLY1 deficiency is a rare genetic disorder caused by mutations in the NGLY1 gene. This disorder presents a wide range of clinical symptoms, and its severity varies among affected individuals. Previous studies have focused on understanding the influence of NGLY1 on energy metabolism, revealing dysregulation in lipid metabolism following NGLY1 deletion. In this study, we investigated the consequences of the loss of NGLY1 on ferroptosis and iron homeostasis using human hepatocellular carcinoma cells, HepG2. Comparative proteomics analysis revealed significant alterations in protein quantities in NGLY1-deficient HepG2 cells, indicating that these cells are under "pro-ferroptotic" stress state. Moreover, dysregulated iron uptake and increased reactive oxygen species production were observed in the absence of NGLY1, indicating a novel perspective on the consequences of the loss of NGLY1. These findings provide important insights into the molecular pathways affected by NGLY1 deletion and may contribute to the development of potential therapeutic strategies for individuals with NGLY1 deficiency.
2025-07-17 | Predicting disease-overarching therapeutic approaches for Congenital Disorders of Glycosylation using multi-OMICS.
Congenital Disorders of Glycosylation (CDG) are a rapidly expanding group of inherited metabolic diseases caused by defects in glycosylation. Although over 190 genetic defects have been identified, effective treatments remain available for only a few. We hypothesized that integrative analysis of multi-omics datasets from individuals with various CDG could uncover common molecular signatures and highlight shared therapeutic targets. We compiled all publicly available RNA sequencing, proteomics and glycoproteomics datasets from patients with PMM2-CDG, ALG1-CDG, SRD5A3-CDG, NGLY1-CDDG, ALG13-CDG and PGM1-CDG, spanning different tissues, including induced cardiomyocytes, human cortical organoids, fibroblasts, and lymphoblasts. Differential expression and glycosylation analyses were performed, followed by Gene Set Enrichment Analysis (GSEA) to identify commonly dysregulated pathways. We then applied the EMUDRA drug prediction algorithm to prioritize candidate compounds capable of reversing these shared molecular signatures. We identified four glycoproteins with consistent differential glycosylation across all eight glycoproteomics datasets. Six glycosylation sites and glycan structures were recurrently altered across CDG and showed partial correction with treatment. Pathway analysis revealed shared disruptions in autophagy, vesicle trafficking, and mitochondrial function. EMUDRA predicted several repurposable drug classes, including muscle relaxants, antioxidants, beta-adrenergic agonists, antibiotics, and NSAIDs, that could reverse key pathway abnormalities, particularly those involving autophagy and N-glycosylation. Most dysregulated pathways were shared across CDG, suggesting the potential for common therapeutic strategies. Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies.
2025-07-11 | Taking the STING out of neurodegenerative disease.
New work from Yang et al. (https://doi.org/10.1084/jem.20242296) provides an exhaustive study of a novel mouse model of NGLY1 deficiency, a devastating neurological disease, and implicates the cGAS-STING pathway in mediating key disease features which can be rescued using an orally administered STING antagonist.
2025-07-11 | The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency.
The STING pathway is increasingly recognized as a key regulator of neuroinflammation in neurodegenerative disease, but its role in noninflammatory conditions remains unclear. We generated a postnatal inducible whole-body Ngly1 knockout mouse (iNgly1-/-) to model NGLY1 deficiency, an early-onset neurodegenerative disorder. iNgly1-/- mice exhibit progressive motor deficits, Purkinje cell loss, and shortened lifespan without evidence of gliosis or immune activation. Cell type-specific deletion of Ngly1 in Purkinje cells or microglia failed to induce disease, suggesting multiple cell-intrinsic and cell-extrinsic signals are required. Genetic ablation of Sting1 in iNgly1-/- mice rescues Purkinje cell loss, improves motor function, and extends lifespan. Single-nucleus RNA sequencing reveals proteostasis disruption in Purkinje cells, altered cerebellar granule cell subpopulations, and STING-dependent suppression of cholesterol biosynthesis in glia. Pharmacological inhibition of STING with an orally bioactive antagonist, VS-X4, significantly mitigates neuropathology and motor disease. These findings identify STING as a key mediator of neuropathology in NGLY1 deficiency and implicate a role of STING in noninflammatory neurological disease.
2025-06-11 | Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants
NGLY1 deficiency is a congenital disorder of deglycosylation, caused by pathogenic variants of the NGLY1 gene. It manifests as global developmental delay, hypo- or alacrima, hypotonia, and a primarily hyperkinetic movement disorder. The NGLY1 enzyme is involved in deglycosylation of misfolded N-glycosylated proteins before their proteasomal degradation, and in the activation of transcription factors that control the expression of proteasomal subunits. Here, we have characterized the pathogenic NGLY1 variants found in three Swiss NGLY deficiency patients, as well as the Arg401* variant found in several patients. Our functional and structural assessment of these variants show that they cause a profound reduction of NGLY1 activity, severely reduced expression of NGLY1 protein, and misprocessing of the transcription factor NFE2L1. Furthermore, transcription of proteasomal subunits and NGLY1 mRNA splicing are impaired by some of these variants. Our structural analysis shows that the Arg390Gln substitution results in destabilization of NGLY1 structure due to a loss of an ionic interaction network of Arg390, and potentially impairment of protein-protein interactions. Our results provide important information on the functional and structural effects of pathogenic NGLY1 variants and pave way for structure-based development of personalized treatment options.
gene therapies
2026-06-27 | Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort.
NGLY1 deficiency is an ultra-rare multisystem disorder characterized by developmental delay, hyperkinetic movement disorder, hypo-/alacrimia, peripheral neuropathy, and elevated transaminases. We conducted a multicenter retrospective study including 15 patients from 11 families to evaluate the clinical, biochemical, and molecular features of the disease. A literature review was also performed, and phenotypic data from published patients were evaluated. All patients presented with developmental delay and dysmorphic facial features. Common neurological findings included abnormal EEG (10/15), seizures (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon reflexes (6/15), and peripheral neuropathy (3/5). Frequent non-neurological features included feeding difficulties (9/15), scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and auditory neuropathy (2/4). Peripheral and auditory neuropathy findings were observed over time. Elevated transaminases were the most common laboratory abnormality (12/14) and were transient in most patients (9/12), followed by low total cholesterol (7/10) and HDL levels (5/10). We identified 10 distinct variants, including two novel variants c.629delA (p.(Lys210SerfsTer14)) and c.1036C > T (p.(Gln346Ter)). Most patients carried homozygous variants, and no clear genotype-phenotype correlation was observed. Our findings expand the clinical and molecular spectrum of NGLY1 deficiency and highlight its dynamic and progressive course, supporting the need for long-term clinical follow-up. NGLY1 deficiency may be considered in patients with neurologic findings and dysmorphic features, especially when transient elevated transaminases and hypolipidemia are also present.
2026-05-11 | Natural history of NGLY1 deficiency: motor function & clinical features.
N-glycanase 1 (NGLY1) Deficiency is an ultra-rare neurodevelopmental disorder caused by biallelic loss-of-function mutations in the NGLY1 gene, leading to severe impairments in neurocognitive and motor function abilities in the affected patient population. Its core clinical features include global developmental delay, hyperkinetic movement disorders, elevation of liver transaminases, (hypo)alacrima, and progressive sensorimotor neuropathy. Due to the range of phenotypes and severity within the confirmed patient population, ongoing characterization of the disease is critical. A prospective natural history study (NHS) was conducted to further elucidate disease phenotypes and examine any changes in neurocognitive or motor function over a one-year period. Fifteen participants, representing roughly 10% of the total identified patient population, were enrolled to complete three onsite visits. Participants in this study exhibited phenotypes previously reported, including core disease phenotypes, hypotonia, scoliosis, musculoskeletal abnormalities, abnormal electroencephalogram (EEG) results, and visual and genitourinary abnormalities. Results from validated neurocognitive and motor function assessments revealed profound global developmental delays in all participants, including communication, gross and fine motor function, and cognitive domains. Age-equivalent scores identified a widening developmental gap between participants and neurotypical peers over time, indicating delayed milestone achievement and/or regression. Although fluctuations were observed, measurements for individual participants were mostly stable over the course of the NHS. Liver transaminase and biomarker N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA) levels were elevated in all participants. Results build on previous studies and inform the selection of potential endpoints for emerging interventional clinical trials, including laboratory values, neurocognitive and motor function assessments, and caregiver reported outcomes.
2026-04-04 | MRI Characterization of Structural Brain Abnormalities in NGLY1 Deficiency
Abstract Key Points Question Is NGLY1 Deficiency associated with consistent alterations in brain structure and do these alterations relate to clinical phenotypes? Findings In this case series of 11 patients with NGLY1 Deficiency, MRI brain scans revealed significant subcortical volume reductions across patient age groups, particularly in the thalamus, caudate, and putamen. Younger patients (<3 years old) showed extensive cortical disruptions suggestive of altered gyrification, while older patients (>3 years old) demonstrated region-specific cortical thickness changes. These alterations were associated with several clinical variables, including the presence of seizures, dysphagia, gait disturbance, EEG abnormalities, sleep disturbance, and hearing abnormalities. Meaning Widespread alterations in cortical and subcortical morphology as assessed by MRI highlight the significant impact NGLY1 Deficiency has on brain development. Associations between morphology and clinical variables suggest that these neuroimaging metrics may serve as useful biomarkers of disease progression and in assessing treatment efficacy. Importance NGLY1 (N-Glycanase 1) Deficiency is an ultra-rare autosomal recessive disorder affecting ∼165 patients worldwide, characterized by developmental delay, hyperkinetic movement disorders, and shortened life expectancy. Despite its severe neurological manifestations, comprehensive neuroimaging characterization has been limited to case reports and small descriptive studies. Objective To investigate alterations in brain morphology in patients with NGLY1 Deficiency and determine whether these metrics associate with clinical phenotypes. Design, Setting, and Participants This case series analyzed real-world MRI scans performed on 11 patients with NGLY1 Deficiency between 1999-2023 at sites across the globe. Ages ranged from 2 to 19 years at scan time (5 female, 6 male). Exposure Molecular diagnosis of NGLY1 Deficiency. Main Outcomes and Measures Cortical and subcortical morphology, including subcortical volume, and cortical thickness, surface area, volume, and curvature, were measured with 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. Z-scores were calculated using normative models from CentileBrain for patients >3 years old or custom models for patients <3 years old. Clinical phenotypes were matched to Human Phenotype Ontology codes. Results 16 scans from 11 patients met quality criteria for analysis. Both age groups (under and over 3 years old) showed significantly reduced subcortical volumes, particularly in bilateral thalamus and putamen. Younger patients demonstrated widespread reductions in cortical surface area, volume, and curvature, indicating altered gyrification patterns. Older patients showed thinner dorsal and thicker ventral cortical regions with limited surface area reductions. Thalamic volume reduction in older patients correlated with gait disturbance, dysphagia, and EEG abnormalities, with additional cortical associations with sleep and hearing abnormalities. Seizure presence in younger patients correlated with altered cortical thickness, surface area, and curvature patterns. Conclusions and Relevance NGLY1 Deficiency is associated with pervasive alterations in brain development affecting both subcortical and cortical morphology. Age-dependent patterns of cortical alterations indicate disrupted neurodevelopmental trajectories that may reflect impaired neuronal migration and/or altered synaptic pruning. Correlations with clinical variables suggest that these measures may serve as useful biomarkers for tracking disease progression and/or treatment efficacy. These findings provide a comprehensive neuroimaging characterization of NGLY1 Deficiency and establish a foundation for understanding brain structure-function relationships in this ultra-rare disorder.
2026-04-01 | Cytosolic Peptide: N-Glycanase (NGLY1)-from Basic Biology to Genetic Disorder, NGLY1 Deficiency.
The cytosolic peptide:N-glycanase (PNGase, NGLY1 in mammals) is an enzyme that removes N-glycans from misfolded glycoproteins. NGLY1 contributes to cytosolic glycan degradation (non-lysosomal glycan degradation) and is one of the quality control systems for newly synthesized proteins, i.e., ER-associated degradation (ERAD). NGLY1 is also responsible for the activation of a transcription factor, NFE2L1, which participates in several stress responses, including regulation of proteasome subunit expression and oxidative stress. In 2012, NGLY1 deficiency, a human genetic disorder caused by the biallelic mutations in the NGLY1 gene, was discovered. Since then, research on the physiological functions of NGLY1 and the pathogenic mechanism of NGLY1 deficiency has expanded rapidly. Here, we will briefly overview the early history of NGLY1 research and then introduce its versatile functions. We will also provide mechanistic insights into the pathogenesis of NGLY1 deficiency based on studies using model animals, such as worms, flies, and rodents.
2026-02-20 | Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats
Abstract Background N-glycanase 1 (NGLY1) Deficiency is an ultra-rare autosomal recessive disorder of deglycosylation caused by loss-of-function mutations in the NGLY1 gene. Patients present with developmental delay, intellectual disability, hyperkinetic movement disorder, elevated liver enzymes, (hypo)alacrima, and peripheral neuropathy. Despite supportive care, many experience early neurological deterioration, with loss of previously attained motor skills by adolescence. Additionally, life-threatening complications are not uncommon, and the published median lifespan of patients is ~13 years. The pathophysiology of NGLY1 Deficiency remains poorly understood, in part due to limited long-term studies in animal models. Notably, Ngly1⁻/⁻ mice (C57BL/6) are embryonically lethal, and prior characterization of Ngly1⁻/⁻ rats was restricted to young adult rat (~7 months old), leaving late-onset phenotypes and potential lifespan reduction unexplored. Methods In the study reported here, longitudinal assessments of phenotypes in Ngly1⁻/⁻ rats were conducted alongside Ngly1⁺/⁻ and Ngly1⁺/⁺ control rats. Survival, motor function, biochemical biomarkers, and brain histopathology were examined in the rats from approximately 6 months to 17–18 months of age. Results Ngly1⁻/⁻ rats exhibited markedly reduced lifespan, progressive neurological decline, and decreased quality of life compared with Ngly1⁺/⁻ and Ngly1⁺/⁺ rats. By 9–10 months of age, ~50% of the Ngly1⁻/⁻ rats had either died or met humane euthanasia criteria due to a severe decline in health. Surviving animals displayed phenotypes mirroring human NGLY1 Deficiency disease progression, such as worsening motor deficits (~92% reduction in rotarod latency and ~82% reduction in rearing) and wide-spread neuroinflammation in multiple brain regions. In contrast, Ngly1⁺/⁻ and Ngly1⁺/⁺ littermates remained healthy and exhibited normal lifespan and aging profiles. Furthermore, histopathological examination of Ngly1⁻/⁻ rats identified significant neuropathological abnormalities that were not present in the control cohorts, including loss of peripheral axons and spinal motor neurons. Conclusion The findings reported here demonstrate that Ngly1⁻/⁻ rats recapitulate the severe, progressive course of NGLY1 Deficiency, including neurodegenerative deterioration, motor deficits, and premature mortality. This extended longitudinal assessment of Ngly1⁻/⁻ rats provides important insights into disease progression and the shortened lifespan reported for human patients.
proteins
2025-08-07 | qPCR results and primers used.
N-glycanase 1 (NGLY1) deficiency is an ultra-rare disease caused by autosomal recessive loss-of-function mutations in the NGLY1 gene. NGLY1 removes N-linked glycans from glycoproteins in the cytoplasm and is thought to help clear misfolded proteins from the endoplasmic reticulum (ER) through the ER associated degradation (ERAD) pathway. Despite this, the physiological significance of NGLY1 in ERAD is not understood. The best characterized substrate of NGLY1 is NRF1, a transcription factor that upregulates proteasome expression and the proteasome bounce-back response. We previously performed a genetic modifier screen using a Drosophila model of NGLY1 deficiency and identified potential modifiers that alter the lethality of the model. We identified two protein-coding variants in Hrd3/SEL1L: S780P and Δ806–809. Both variants are localized to the SEL1L cytoplasmic tail, an uncharacterized domain. SEL1L is a component of the ERAD complex that retrotranslocates misfolded proteins from the ER to the cytoplasm for degradation. We used CRISPR to generate fly lines carrying these SEL1L variants in a common genetic background and tested them with our model of NGLY1 deficiency. Validating our previous screen, the SEL1LS780P and SEL1LΔ806-809 variants increased the survival of the NGLY1 deficiency model, compared to the SEL1LS780 variant. To determine how these SEL1L variants were modifying lethality in NGLY1 deficiency, we interrogated the ERAD and NRF1 signaling pathways. We found that the SEL1LS780P and SEL1LΔ806-809 variants improve resistance to ER stress, with enhanced ERAD function as a likely contributing mechanism. This effect depends on NGLY1 activity, further implicating NGLY1 in general ERAD function. We also found that, in heterozygous NGLY1 null flies, these variants protect against some defects like increased lethality caused by proteasome inhibition. These results provide new insights into the role of SEL1L in the disease pathogenesis of NGLY1 deficiency. SEL1L is a strong candidate modifier gene in patients, where variability in presentation is common.
2025-08-07 | Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity.
N-glycanase 1 (NGLY1) deficiency is an ultra-rare disease caused by autosomal recessive loss-of-function mutations in the NGLY1 gene. NGLY1 removes N-linked glycans from glycoproteins in the cytoplasm and is thought to help clear misfolded proteins from the endoplasmic reticulum (ER) through the ER associated degradation (ERAD) pathway. Despite this, the physiological significance of NGLY1 in ERAD is not understood. The best characterized substrate of NGLY1 is NRF1, a transcription factor that upregulates proteasome expression and the proteasome bounce-back response. We previously performed a genetic modifier screen using a Drosophila model of NGLY1 deficiency and identified potential modifiers that alter the lethality of the model. We identified two protein-coding variants in Hrd3/SEL1L: S780P and Δ806-809. Both variants are localized to the SEL1L cytoplasmic tail, an uncharacterized domain. SEL1L is a component of the ERAD complex that retrotranslocates misfolded proteins from the ER to the cytoplasm for degradation. We used CRISPR to generate fly lines carrying these SEL1L variants in a common genetic background and tested them with our model of NGLY1 deficiency. Validating our previous screen, the SEL1LS780P and SEL1LΔ806-809 variants increased the survival of the NGLY1 deficiency model, compared to the SEL1LS780 variant. To determine how these SEL1L variants were modifying lethality in NGLY1 deficiency, we interrogated the ERAD and NRF1 signaling pathways. We found that the SEL1LS780P and SEL1LΔ806-809 variants improve resistance to ER stress, with enhanced ERAD function as a likely contributing mechanism. This effect depends on NGLY1 activity, further implicating NGLY1 in general ERAD function. We also found that, in heterozygous NGLY1 null flies, these variants protect against some defects like increased lethality caused by proteasome inhibition. These results provide new insights into the role of SEL1L in the disease pathogenesis of NGLY1 deficiency. SEL1L is a strong candidate modifier gene in patients, where variability in presentation is common.
2025-03-11 | Natural SEL1L variants modify ERAD, proteasome function, and survival in a Drosophila model of NGLY1 deficiency
ABSTRACT N-glycanase 1 (NGLY1) deficiency is an ultra-rare disease caused by autosomal recessive loss-of-function mutations in the NGLY1 gene. NGLY1 removes N-linked glycans from glycoproteins in the cytoplasm and is thought to help clear misfolded proteins from the endoplasmic reticulum (ER) through the ER associated degradation (ERAD) pathway. Despite this, the physiological significance of NGLY1 in ERAD is not understood. The best characterized substrate of NGLY1 is NRF1, a transcription factor that upregulates proteasome expression and the proteasome bounce-back response. We previously performed a genetic modifier screen using a Drosophila model of NGLY1 deficiency and identified potential modifiers that alter the lethality of the model. We identified two protein-coding variants in Hrd3 / SEL1L : S780P and Δ806-809 . Both variants are localized to the SEL1L cytoplasmic tail, an uncharacterized domain. SEL1L is a component of the ERAD complex that retrotranslocates misfolded proteins from the ER to the cytoplasm for degradation. We used CRISPR to generate fly lines carrying these SEL1L variants in a common genetic background and tested them with our model of NGLY1 deficiency. Validating our previous screen, the SEL1L P780 and SEL1L Δ806-809 variants increase the survival of the NGLY1 deficiency model, compared to the SEL1L S780 variant. To determine how these SEL1L variants were modifying lethality in NGLY1 deficiency, we interrogated the ERAD and NRF1 signaling pathways. We found that the SEL1L P780 and SEL1L Δ806-809 variants improve ERAD function in an NGLY1- dependent manner, further implicating NGLY1 in general ERAD function. We also found that these variants protect against changes in larval size and survival caused by proteasome inhibition in heterozygous NGLY1 null flies. These results provide new insights into the role of SEL1L in the disease pathogenesis of NGLY1 deficiency. SEL1L is a strong candidate modifier gene in patients, where variability in presentation is common. AUTHOR’S SUMMARY NGLY1 deficiency is a debilitating rare genetic disorder. There are currently no treatment options for NGLY1 deficiency and NGLY1 biology remains poorly understood. We previously performed a genetic modifier screen in a Drosophila model of NGLY1 deficiency and identified a number of candidate modifier genes that impacted the survival of our model. Modifier genes can help reveal NGLY1 biology and NGLY1 deficiency disease pathogenesis. In this study, we follow-up on two natural protein-coding variants of Hrd3 (the fly version of the human gene, SEL1L ) that increased the survival of our NGLY1 deficiency model. SEL1L is a critical component of an important quality control pathway called the endoplasmic reticulum associated degradation (ERAD) pathway. We discovered that these SEL1L variants enhance ERAD and modify NGLY1 deficiency sensitivity to proteasome inhibition. This study confirms SEL1L as an important modifier gene of NGLY1 deficiency. Further study of the ERAD and proteasome degradation pathways may reveal additional candidate modifier genes of NGLY1 deficiency and potential targets for therapeutic development.
small molecules
2025-08-14 | Comparative proteomics of HepG2 cells reveals NGLY1 as an important regulator of ferroptosis resistance and iron uptake.
NGLY1 deficiency is a rare genetic disorder caused by mutations in the NGLY1 gene. This disorder presents a wide range of clinical symptoms, and its severity varies among affected individuals. Previous studies have focused on understanding the influence of NGLY1 on energy metabolism, revealing dysregulation in lipid metabolism following NGLY1 deletion. In this study, we investigated the consequences of the loss of NGLY1 on ferroptosis and iron homeostasis using human hepatocellular carcinoma cells, HepG2. Comparative proteomics analysis revealed significant alterations in protein quantities in NGLY1-deficient HepG2 cells, indicating that these cells are under "pro-ferroptotic" stress state. Moreover, dysregulated iron uptake and increased reactive oxygen species production were observed in the absence of NGLY1, indicating a novel perspective on the consequences of the loss of NGLY1. These findings provide important insights into the molecular pathways affected by NGLY1 deletion and may contribute to the development of potential therapeutic strategies for individuals with NGLY1 deficiency.
2025-07-17 | Predicting disease-overarching therapeutic approaches for Congenital Disorders of Glycosylation using multi-OMICS.
Congenital Disorders of Glycosylation (CDG) are a rapidly expanding group of inherited metabolic diseases caused by defects in glycosylation. Although over 190 genetic defects have been identified, effective treatments remain available for only a few. We hypothesized that integrative analysis of multi-omics datasets from individuals with various CDG could uncover common molecular signatures and highlight shared therapeutic targets. We compiled all publicly available RNA sequencing, proteomics and glycoproteomics datasets from patients with PMM2-CDG, ALG1-CDG, SRD5A3-CDG, NGLY1-CDDG, ALG13-CDG and PGM1-CDG, spanning different tissues, including induced cardiomyocytes, human cortical organoids, fibroblasts, and lymphoblasts. Differential expression and glycosylation analyses were performed, followed by Gene Set Enrichment Analysis (GSEA) to identify commonly dysregulated pathways. We then applied the EMUDRA drug prediction algorithm to prioritize candidate compounds capable of reversing these shared molecular signatures. We identified four glycoproteins with consistent differential glycosylation across all eight glycoproteomics datasets. Six glycosylation sites and glycan structures were recurrently altered across CDG and showed partial correction with treatment. Pathway analysis revealed shared disruptions in autophagy, vesicle trafficking, and mitochondrial function. EMUDRA predicted several repurposable drug classes, including muscle relaxants, antioxidants, beta-adrenergic agonists, antibiotics, and NSAIDs, that could reverse key pathway abnormalities, particularly those involving autophagy and N-glycosylation. Most dysregulated pathways were shared across CDG, suggesting the potential for common therapeutic strategies. Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies.
2025-07-11 | Taking the STING out of neurodegenerative disease.
New work from Yang et al. (https://doi.org/10.1084/jem.20242296) provides an exhaustive study of a novel mouse model of NGLY1 deficiency, a devastating neurological disease, and implicates the cGAS-STING pathway in mediating key disease features which can be rescued using an orally administered STING antagonist.
2025-07-11 | The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency.
The STING pathway is increasingly recognized as a key regulator of neuroinflammation in neurodegenerative disease, but its role in noninflammatory conditions remains unclear. We generated a postnatal inducible whole-body Ngly1 knockout mouse (iNgly1-/-) to model NGLY1 deficiency, an early-onset neurodegenerative disorder. iNgly1-/- mice exhibit progressive motor deficits, Purkinje cell loss, and shortened lifespan without evidence of gliosis or immune activation. Cell type-specific deletion of Ngly1 in Purkinje cells or microglia failed to induce disease, suggesting multiple cell-intrinsic and cell-extrinsic signals are required. Genetic ablation of Sting1 in iNgly1-/- mice rescues Purkinje cell loss, improves motor function, and extends lifespan. Single-nucleus RNA sequencing reveals proteostasis disruption in Purkinje cells, altered cerebellar granule cell subpopulations, and STING-dependent suppression of cholesterol biosynthesis in glia. Pharmacological inhibition of STING with an orally bioactive antagonist, VS-X4, significantly mitigates neuropathology and motor disease. These findings identify STING as a key mediator of neuropathology in NGLY1 deficiency and implicate a role of STING in noninflammatory neurological disease.
2025-06-11 | Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants
NGLY1 deficiency is a congenital disorder of deglycosylation, caused by pathogenic variants of the NGLY1 gene. It manifests as global developmental delay, hypo- or alacrima, hypotonia, and a primarily hyperkinetic movement disorder. The NGLY1 enzyme is involved in deglycosylation of misfolded N-glycosylated proteins before their proteasomal degradation, and in the activation of transcription factors that control the expression of proteasomal subunits. Here, we have characterized the pathogenic NGLY1 variants found in three Swiss NGLY deficiency patients, as well as the Arg401* variant found in several patients. Our functional and structural assessment of these variants show that they cause a profound reduction of NGLY1 activity, severely reduced expression of NGLY1 protein, and misprocessing of the transcription factor NFE2L1. Furthermore, transcription of proteasomal subunits and NGLY1 mRNA splicing are impaired by some of these variants. Our structural analysis shows that the Arg390Gln substitution results in destabilization of NGLY1 structure due to a loss of an ionic interaction network of Arg390, and potentially impairment of protein-protein interactions. Our results provide important information on the functional and structural effects of pathogenic NGLY1 variants and pave way for structure-based development of personalized treatment options.
gene therapies
2026-06-27 | Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort.
NGLY1 deficiency is an ultra-rare multisystem disorder characterized by developmental delay, hyperkinetic movement disorder, hypo-/alacrimia, peripheral neuropathy, and elevated transaminases. We conducted a multicenter retrospective study including 15 patients from 11 families to evaluate the clinical, biochemical, and molecular features of the disease. A literature review was also performed, and phenotypic data from published patients were evaluated. All patients presented with developmental delay and dysmorphic facial features. Common neurological findings included abnormal EEG (10/15), seizures (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon reflexes (6/15), and peripheral neuropathy (3/5). Frequent non-neurological features included feeding difficulties (9/15), scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and auditory neuropathy (2/4). Peripheral and auditory neuropathy findings were observed over time. Elevated transaminases were the most common laboratory abnormality (12/14) and were transient in most patients (9/12), followed by low total cholesterol (7/10) and HDL levels (5/10). We identified 10 distinct variants, including two novel variants c.629delA (p.(Lys210SerfsTer14)) and c.1036C > T (p.(Gln346Ter)). Most patients carried homozygous variants, and no clear genotype-phenotype correlation was observed. Our findings expand the clinical and molecular spectrum of NGLY1 deficiency and highlight its dynamic and progressive course, supporting the need for long-term clinical follow-up. NGLY1 deficiency may be considered in patients with neurologic findings and dysmorphic features, especially when transient elevated transaminases and hypolipidemia are also present.
2026-05-11 | Natural history of NGLY1 deficiency: motor function & clinical features.
N-glycanase 1 (NGLY1) Deficiency is an ultra-rare neurodevelopmental disorder caused by biallelic loss-of-function mutations in the NGLY1 gene, leading to severe impairments in neurocognitive and motor function abilities in the affected patient population. Its core clinical features include global developmental delay, hyperkinetic movement disorders, elevation of liver transaminases, (hypo)alacrima, and progressive sensorimotor neuropathy. Due to the range of phenotypes and severity within the confirmed patient population, ongoing characterization of the disease is critical. A prospective natural history study (NHS) was conducted to further elucidate disease phenotypes and examine any changes in neurocognitive or motor function over a one-year period. Fifteen participants, representing roughly 10% of the total identified patient population, were enrolled to complete three onsite visits. Participants in this study exhibited phenotypes previously reported, including core disease phenotypes, hypotonia, scoliosis, musculoskeletal abnormalities, abnormal electroencephalogram (EEG) results, and visual and genitourinary abnormalities. Results from validated neurocognitive and motor function assessments revealed profound global developmental delays in all participants, including communication, gross and fine motor function, and cognitive domains. Age-equivalent scores identified a widening developmental gap between participants and neurotypical peers over time, indicating delayed milestone achievement and/or regression. Although fluctuations were observed, measurements for individual participants were mostly stable over the course of the NHS. Liver transaminase and biomarker N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA) levels were elevated in all participants. Results build on previous studies and inform the selection of potential endpoints for emerging interventional clinical trials, including laboratory values, neurocognitive and motor function assessments, and caregiver reported outcomes.
2026-04-04 | MRI Characterization of Structural Brain Abnormalities in NGLY1 Deficiency
Abstract Key Points Question Is NGLY1 Deficiency associated with consistent alterations in brain structure and do these alterations relate to clinical phenotypes? Findings In this case series of 11 patients with NGLY1 Deficiency, MRI brain scans revealed significant subcortical volume reductions across patient age groups, particularly in the thalamus, caudate, and putamen. Younger patients (<3 years old) showed extensive cortical disruptions suggestive of altered gyrification, while older patients (>3 years old) demonstrated region-specific cortical thickness changes. These alterations were associated with several clinical variables, including the presence of seizures, dysphagia, gait disturbance, EEG abnormalities, sleep disturbance, and hearing abnormalities. Meaning Widespread alterations in cortical and subcortical morphology as assessed by MRI highlight the significant impact NGLY1 Deficiency has on brain development. Associations between morphology and clinical variables suggest that these neuroimaging metrics may serve as useful biomarkers of disease progression and in assessing treatment efficacy. Importance NGLY1 (N-Glycanase 1) Deficiency is an ultra-rare autosomal recessive disorder affecting ∼165 patients worldwide, characterized by developmental delay, hyperkinetic movement disorders, and shortened life expectancy. Despite its severe neurological manifestations, comprehensive neuroimaging characterization has been limited to case reports and small descriptive studies. Objective To investigate alterations in brain morphology in patients with NGLY1 Deficiency and determine whether these metrics associate with clinical phenotypes. Design, Setting, and Participants This case series analyzed real-world MRI scans performed on 11 patients with NGLY1 Deficiency between 1999-2023 at sites across the globe. Ages ranged from 2 to 19 years at scan time (5 female, 6 male). Exposure Molecular diagnosis of NGLY1 Deficiency. Main Outcomes and Measures Cortical and subcortical morphology, including subcortical volume, and cortical thickness, surface area, volume, and curvature, were measured with 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. Z-scores were calculated using normative models from CentileBrain for patients >3 years old or custom models for patients <3 years old. Clinical phenotypes were matched to Human Phenotype Ontology codes. Results 16 scans from 11 patients met quality criteria for analysis. Both age groups (under and over 3 years old) showed significantly reduced subcortical volumes, particularly in bilateral thalamus and putamen. Younger patients demonstrated widespread reductions in cortical surface area, volume, and curvature, indicating altered gyrification patterns. Older patients showed thinner dorsal and thicker ventral cortical regions with limited surface area reductions. Thalamic volume reduction in older patients correlated with gait disturbance, dysphagia, and EEG abnormalities, with additional cortical associations with sleep and hearing abnormalities. Seizure presence in younger patients correlated with altered cortical thickness, surface area, and curvature patterns. Conclusions and Relevance NGLY1 Deficiency is associated with pervasive alterations in brain development affecting both subcortical and cortical morphology. Age-dependent patterns of cortical alterations indicate disrupted neurodevelopmental trajectories that may reflect impaired neuronal migration and/or altered synaptic pruning. Correlations with clinical variables suggest that these measures may serve as useful biomarkers for tracking disease progression and/or treatment efficacy. These findings provide a comprehensive neuroimaging characterization of NGLY1 Deficiency and establish a foundation for understanding brain structure-function relationships in this ultra-rare disorder.
2026-04-01 | Cytosolic Peptide: N-Glycanase (NGLY1)-from Basic Biology to Genetic Disorder, NGLY1 Deficiency.
The cytosolic peptide:N-glycanase (PNGase, NGLY1 in mammals) is an enzyme that removes N-glycans from misfolded glycoproteins. NGLY1 contributes to cytosolic glycan degradation (non-lysosomal glycan degradation) and is one of the quality control systems for newly synthesized proteins, i.e., ER-associated degradation (ERAD). NGLY1 is also responsible for the activation of a transcription factor, NFE2L1, which participates in several stress responses, including regulation of proteasome subunit expression and oxidative stress. In 2012, NGLY1 deficiency, a human genetic disorder caused by the biallelic mutations in the NGLY1 gene, was discovered. Since then, research on the physiological functions of NGLY1 and the pathogenic mechanism of NGLY1 deficiency has expanded rapidly. Here, we will briefly overview the early history of NGLY1 research and then introduce its versatile functions. We will also provide mechanistic insights into the pathogenesis of NGLY1 deficiency based on studies using model animals, such as worms, flies, and rodents.
2026-02-20 | Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats
Abstract Background N-glycanase 1 (NGLY1) Deficiency is an ultra-rare autosomal recessive disorder of deglycosylation caused by loss-of-function mutations in the NGLY1 gene. Patients present with developmental delay, intellectual disability, hyperkinetic movement disorder, elevated liver enzymes, (hypo)alacrima, and peripheral neuropathy. Despite supportive care, many experience early neurological deterioration, with loss of previously attained motor skills by adolescence. Additionally, life-threatening complications are not uncommon, and the published median lifespan of patients is ~13 years. The pathophysiology of NGLY1 Deficiency remains poorly understood, in part due to limited long-term studies in animal models. Notably, Ngly1⁻/⁻ mice (C57BL/6) are embryonically lethal, and prior characterization of Ngly1⁻/⁻ rats was restricted to young adult rat (~7 months old), leaving late-onset phenotypes and potential lifespan reduction unexplored. Methods In the study reported here, longitudinal assessments of phenotypes in Ngly1⁻/⁻ rats were conducted alongside Ngly1⁺/⁻ and Ngly1⁺/⁺ control rats. Survival, motor function, biochemical biomarkers, and brain histopathology were examined in the rats from approximately 6 months to 17–18 months of age. Results Ngly1⁻/⁻ rats exhibited markedly reduced lifespan, progressive neurological decline, and decreased quality of life compared with Ngly1⁺/⁻ and Ngly1⁺/⁺ rats. By 9–10 months of age, ~50% of the Ngly1⁻/⁻ rats had either died or met humane euthanasia criteria due to a severe decline in health. Surviving animals displayed phenotypes mirroring human NGLY1 Deficiency disease progression, such as worsening motor deficits (~92% reduction in rotarod latency and ~82% reduction in rearing) and wide-spread neuroinflammation in multiple brain regions. In contrast, Ngly1⁺/⁻ and Ngly1⁺/⁺ littermates remained healthy and exhibited normal lifespan and aging profiles. Furthermore, histopathological examination of Ngly1⁻/⁻ rats identified significant neuropathological abnormalities that were not present in the control cohorts, including loss of peripheral axons and spinal motor neurons. Conclusion The findings reported here demonstrate that Ngly1⁻/⁻ rats recapitulate the severe, progressive course of NGLY1 Deficiency, including neurodegenerative deterioration, motor deficits, and premature mortality. This extended longitudinal assessment of Ngly1⁻/⁻ rats provides important insights into disease progression and the shortened lifespan reported for human patients.
proteins
2025-08-07 | qPCR results and primers used.
N-glycanase 1 (NGLY1) deficiency is an ultra-rare disease caused by autosomal recessive loss-of-function mutations in the NGLY1 gene. NGLY1 removes N-linked glycans from glycoproteins in the cytoplasm and is thought to help clear misfolded proteins from the endoplasmic reticulum (ER) through the ER associated degradation (ERAD) pathway. Despite this, the physiological significance of NGLY1 in ERAD is not understood. The best characterized substrate of NGLY1 is NRF1, a transcription factor that upregulates proteasome expression and the proteasome bounce-back response. We previously performed a genetic modifier screen using a Drosophila model of NGLY1 deficiency and identified potential modifiers that alter the lethality of the model. We identified two protein-coding variants in Hrd3/SEL1L: S780P and Δ806–809. Both variants are localized to the SEL1L cytoplasmic tail, an uncharacterized domain. SEL1L is a component of the ERAD complex that retrotranslocates misfolded proteins from the ER to the cytoplasm for degradation. We used CRISPR to generate fly lines carrying these SEL1L variants in a common genetic background and tested them with our model of NGLY1 deficiency. Validating our previous screen, the SEL1LS780P and SEL1LΔ806-809 variants increased the survival of the NGLY1 deficiency model, compared to the SEL1LS780 variant. To determine how these SEL1L variants were modifying lethality in NGLY1 deficiency, we interrogated the ERAD and NRF1 signaling pathways. We found that the SEL1LS780P and SEL1LΔ806-809 variants improve resistance to ER stress, with enhanced ERAD function as a likely contributing mechanism. This effect depends on NGLY1 activity, further implicating NGLY1 in general ERAD function. We also found that, in heterozygous NGLY1 null flies, these variants protect against some defects like increased lethality caused by proteasome inhibition. These results provide new insights into the role of SEL1L in the disease pathogenesis of NGLY1 deficiency. SEL1L is a strong candidate modifier gene in patients, where variability in presentation is common.
2025-08-07 | Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity.
N-glycanase 1 (NGLY1) deficiency is an ultra-rare disease caused by autosomal recessive loss-of-function mutations in the NGLY1 gene. NGLY1 removes N-linked glycans from glycoproteins in the cytoplasm and is thought to help clear misfolded proteins from the endoplasmic reticulum (ER) through the ER associated degradation (ERAD) pathway. Despite this, the physiological significance of NGLY1 in ERAD is not understood. The best characterized substrate of NGLY1 is NRF1, a transcription factor that upregulates proteasome expression and the proteasome bounce-back response. We previously performed a genetic modifier screen using a Drosophila model of NGLY1 deficiency and identified potential modifiers that alter the lethality of the model. We identified two protein-coding variants in Hrd3/SEL1L: S780P and Δ806-809. Both variants are localized to the SEL1L cytoplasmic tail, an uncharacterized domain. SEL1L is a component of the ERAD complex that retrotranslocates misfolded proteins from the ER to the cytoplasm for degradation. We used CRISPR to generate fly lines carrying these SEL1L variants in a common genetic background and tested them with our model of NGLY1 deficiency. Validating our previous screen, the SEL1LS780P and SEL1LΔ806-809 variants increased the survival of the NGLY1 deficiency model, compared to the SEL1LS780 variant. To determine how these SEL1L variants were modifying lethality in NGLY1 deficiency, we interrogated the ERAD and NRF1 signaling pathways. We found that the SEL1LS780P and SEL1LΔ806-809 variants improve resistance to ER stress, with enhanced ERAD function as a likely contributing mechanism. This effect depends on NGLY1 activity, further implicating NGLY1 in general ERAD function. We also found that, in heterozygous NGLY1 null flies, these variants protect against some defects like increased lethality caused by proteasome inhibition. These results provide new insights into the role of SEL1L in the disease pathogenesis of NGLY1 deficiency. SEL1L is a strong candidate modifier gene in patients, where variability in presentation is common.
2025-03-11 | Natural SEL1L variants modify ERAD, proteasome function, and survival in a Drosophila model of NGLY1 deficiency
ABSTRACT N-glycanase 1 (NGLY1) deficiency is an ultra-rare disease caused by autosomal recessive loss-of-function mutations in the NGLY1 gene. NGLY1 removes N-linked glycans from glycoproteins in the cytoplasm and is thought to help clear misfolded proteins from the endoplasmic reticulum (ER) through the ER associated degradation (ERAD) pathway. Despite this, the physiological significance of NGLY1 in ERAD is not understood. The best characterized substrate of NGLY1 is NRF1, a transcription factor that upregulates proteasome expression and the proteasome bounce-back response. We previously performed a genetic modifier screen using a Drosophila model of NGLY1 deficiency and identified potential modifiers that alter the lethality of the model. We identified two protein-coding variants in Hrd3 / SEL1L : S780P and Δ806-809 . Both variants are localized to the SEL1L cytoplasmic tail, an uncharacterized domain. SEL1L is a component of the ERAD complex that retrotranslocates misfolded proteins from the ER to the cytoplasm for degradation. We used CRISPR to generate fly lines carrying these SEL1L variants in a common genetic background and tested them with our model of NGLY1 deficiency. Validating our previous screen, the SEL1L P780 and SEL1L Δ806-809 variants increase the survival of the NGLY1 deficiency model, compared to the SEL1L S780 variant. To determine how these SEL1L variants were modifying lethality in NGLY1 deficiency, we interrogated the ERAD and NRF1 signaling pathways. We found that the SEL1L P780 and SEL1L Δ806-809 variants improve ERAD function in an NGLY1- dependent manner, further implicating NGLY1 in general ERAD function. We also found that these variants protect against changes in larval size and survival caused by proteasome inhibition in heterozygous NGLY1 null flies. These results provide new insights into the role of SEL1L in the disease pathogenesis of NGLY1 deficiency. SEL1L is a strong candidate modifier gene in patients, where variability in presentation is common. AUTHOR’S SUMMARY NGLY1 deficiency is a debilitating rare genetic disorder. There are currently no treatment options for NGLY1 deficiency and NGLY1 biology remains poorly understood. We previously performed a genetic modifier screen in a Drosophila model of NGLY1 deficiency and identified a number of candidate modifier genes that impacted the survival of our model. Modifier genes can help reveal NGLY1 biology and NGLY1 deficiency disease pathogenesis. In this study, we follow-up on two natural protein-coding variants of Hrd3 (the fly version of the human gene, SEL1L ) that increased the survival of our NGLY1 deficiency model. SEL1L is a critical component of an important quality control pathway called the endoplasmic reticulum associated degradation (ERAD) pathway. We discovered that these SEL1L variants enhance ERAD and modify NGLY1 deficiency sensitivity to proteasome inhibition. This study confirms SEL1L as an important modifier gene of NGLY1 deficiency. Further study of the ERAD and proteasome degradation pathways may reveal additional candidate modifier genes of NGLY1 deficiency and potential targets for therapeutic development.
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Drug Discovery Landscape
3 orphan drug designations for Alacrimia-choreoathetosis-liver dysfunction syndrome.
3 orphan drug designations for Alacrimia-choreoathetosis-liver dysfunction syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Adeno-associated virus serotype 9 encoding human NGLY1 gene | gene therapies | EMA | — | Voisin Consulting Life Sciences |
Adeno-associated virus serotype 9 virus particle containing viral DNA that includes an expression cassette containing the human NGLY1 gene coding sequence | gene therapies | FDA | Grace Science, LLC | |
Aripiprazole | small molecules | FDA | — | Perlara PBC |
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