NGLY1 deficiency
NGLY1 deficiency is a very rare genetic disorder caused by biallelic pathogenic variants in NGLY1. It is an autosomal recessive disorder. Errors in deglycosylation are responsible for the symptoms of this condition. Clinically, most affected individuals display developmental delay, lack of tears, elevated liver transaminases and a movement disorder. NGLY1 deficiency is difficult to diagnose, and most individuals have been identified by exome sequencing.
NGLY1 deficiency causes a dysfunction in the endoplasmic reticulum-associated degradation pathway. NGLY1 encodes an enzyme, N-glycanase 1, that cleaves N-glycans. Without N-glycanase, N-glycosylated proteins that are misfolded in the endoplasmic reticulum cannot be degraded, and thus accumulate in the cytoplasm of cells.
Signs and symptoms
Four common findings have been identified in a majority of patients: developmental delay or intellectual disability of varying degrees, lack of or greatly reduced tears, elevated liver transaminases, and a complex movement disorder. The elevated liver enzymes often resolve in childhood. In addition, approximately 50% of patients described with NGLY1 deficiency have seizures, which can vary in their difficulty to control. Other symptoms that have been reported in affected individuals include sleep apnea, constipation, scoliosis, oral motor defects, auditory neuropathy and peripheral neuropathy.Diagnosis
NGLY1 deficiency can be suspected based on clinical findings, however confirmation of the diagnosis requires the identification of biallelic pathogenic variants in NGLY1 through genetic testing. Traditional screening tests utilized for congenital disorders of glycosylation, including carbohydrate deficient transferrin are not diagnostic in NGLY1 deficiency. To date all variants identified as being causative of NGLY1 deficiency have been sequence variants, rather than copy number variants. This spectrum may change as additional cases are identified. A common nonsense variant accounts for approximately a third of pathogenic variants identified, and is associated with a more severe clinical course.There is also a biomarker for NGLY1 deficiency. When the NGLY1 protein is missing or not functioning correctly, a specific molecule called GlcNAc-Asn accumulates. GNA is elevated in individuals with NGLY1 deficiency compared to individuals without the disease. Elevated GNA alone is not enough to confirm an NGLY1 deficiency diagnosis, but in combination with molecular genetic testing and clinical findings, it can provides additional support for NGLY1 deficiency.