Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort
Molecular Genetics and Metabolism, vol.148, no.4, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 148 Issue: 4
- Publication Date: 2026
- Doi Number: 10.1016/j.ymgme.2026.110195
- Journal Name: Molecular Genetics and Metabolism
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, EMBASE, MEDLINE, Academic Search Ultimate (EBSCO)
- Keywords: Congenital disorder of deglycosylation, Developmental delay, Dysmorphic features, Hypolipidemia, NGLY1 deficiency, Transient elevated transaminases
- Hacettepe University Affiliated: Yes
Abstract
Background: NGLY1 deficiency is an ultra-rare multisystem disorder characterized by developmental delay, hyperkinetic movement disorder, hypo−/alacrimia, peripheral neuropathy, and elevated transaminases. Methods: 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. Results: 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. Conclusion: 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.