Shedding light on NGLY1 deficiency: a call for awareness and support

Abstract

AbstractNGLY1 deficiency is an ultra-rare autosomal recessive disorder caused by loss of function variants in the NGLY1 gene, representing the first known congenital disorder of deglycosylation. The disorder is characterized by a range of core features, including global developmental delay and/or intellectual disability, hyperkinetic movement disorder, transient elevation of liver transaminases, hypo- or alacrima, and peripheral neuropathy. Additional symptoms such as microcephaly, hypotonia, EEG abnormalities, brain imaging abnormalities, GI disturbances, and a history of intrauterine growth restriction have been reported in some cases. NGLY1 gene mutations lead to reduced or absent N-glycanase 1 activity, resulting in the accumulation of abnormal glycoproteins within the endoplasmic reticulum and impairing protein quality control mechanisms. Diagnosis is primarily achieved through genetic testing, while the identification of the biomarker GlcNAc-Asn may facilitate diagnosis rates. Treatment options are currently limited to supportive care, although gene therapy is being developed. To advance understanding and intervention in NGLY1 deficiency, participation in patient registries, natural history studies, and interventional research is crucial. Genetic counseling is strongly recommended for carriers and individuals at risk, with consideration given to DNA preservation for future evaluations and targeted treatments.