Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort.

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.