Purpose The endoplasmic reticulum-associated degradation (ERAD) pathway is responsible for the translocation of misfolded proteins across the ER membrane into the cytosol for subsequent degradation by the proteasome. In order to understand the spectrum of clinical and molecular findings in a complex neurological syndrome, we studied a series of eight patients with inherited deficiency of N-glycanase 1 (NGLY1), a novel disorder of cytosolic ERAD dysfunction. Methods Whole-genome, whole-exome or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. Results All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypo- or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. Conclusions NGLY1 deficiency is a novel autosomal recessive disorder of the ERAD pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a more broad range of mutations are detected.

Fifty-four parents/caretakers of children with cerebral palsy were surveyed regarding their use of antisialorrheic medication for excessive drooling. Glycopyrrolate was used by 37 of 41 respondents, with significant improvement in drooling noted in the vast majority (95%) of cases as indicated by a five-point rating scale. Side effects (dry mouth, thick secretions, urinary retention, or flushing) surfaced in almost half (44%) of the patients but necessitated discontinuation of pharmacologic treatment in less than a third. While larger clinical studies are needed, our preliminary data indicate a trial of glycopyrrolate should be considered in children with cerebral palsy where drooling is a significant problem.

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