Multi-systemic involvement in NGLY1-related disorder caused by two novel mutations.

NGLY1-related disorder is a newly described autosomal recessive condition characterized by neurological, hepatic, ophthalmological findings and associated with dysmorphic features, constipation and scoliosis. It is caused by mutations in NGLY1, which encodes an enzyme, N-glycanase 1, involved in deglycosylation of glycoproteins, an essential step in the endoplasmic reticulum-associated degradation (ERAD) pathway. The disorder has been described in eight patients. We investigated the molecular basis and phenotype of NGLY1-related disorder in an additional patient. The proband is a 14-year-old who presented in early infancy with profound hypotonia and elevated transaminases. Liver biopsy showed lipid accumulation with dilated endoplasmic reticulum. He exhibited global developmental delay, acquired microcephaly, seizures, involuntary body movements, muscle atrophy, absent reflexes, and poor growth. He had multiple procedures for lacrimal duct stenosis and strabismus and had intractable blepharitis. He had severe osteopenia and persistent hypocholesterolemia. Whole exome sequencing revealed two novel variants in NGLY1: a truncating mutation, c.347C > G (p.S116X), and a splicing mutation, c.881 + 5G (p.IVS5 + 5G>T), predicted to abolish the splice donor site of exon 5. This study, along with previously reported cases, suggests that mutations in NGLY1 cause a recognizable phenotype and targeted sequencing should be considered in patients with typical presentation. This study expands the molecular spectrum of NGLY1-related condition and suggests that osteopenia and hypocholesterolemia may be part of the phenotype.