NGLY1 deficiency (or N-Glycanase deficiency) is an extremely rare genetic disorder.

Global developmental delay (often severe), neurological impairment, movement disorder and hypotonia are characteristic features of N-Glycanase deficiency

Almost all patients have difficulty producing tears and present abnormally on EEGs.

What are the symptoms / features?

In addition to global developmental delay, neurological impairment, movement disorder and hypotonia, there are some symptoms that only appear in subgroups of the patient population. 
Each of the following symptoms has been found in at least half of all patients: 
  • A lack of tears (alacrima or hypolacrima): While patients have some moisture in their eyes, they have difficulty producing tear drops when crying.
  • Liver dysfunction: Patients present with elevated liver transaminases such as AST, ALT and sometimes AFP. In particular, alpha-fetoprotein (AFP) may be extremely elevated while young. Liver values trend toward the normal range over time.
  • A smaller head (microcephaly): Patients tend to have a smaller head circumference (around the 5th percentile).
  • Diminished reflexes: Some patients do not respond at all or barely respond to reflex tests.
  • (As-yet) unidentified material stored in liver cells: There appears to be something stored in the cytoplasm of liver cells.
  • Seizures: About half of all patients have observable seizures, but many of them are not recognizable to non-experts as seizures. Common seizure types include sudden jerks or startles (myoclonic), drops (atonic) and staring spells (absence). Patient EEGs are often described as "abnormal."
In N-glycanase deficiency, the cells of the body cannot synthesize the enzyme N-Glycanase. 

N-Glycanase deficiency is recessive: when parents are carriers, they have a 25% chance of producing a child with the disorder for each pregnancy.

We are fortunate that N-Glycanase was studied by the glycobiology community long before the discovery of the disorder.

N-Glycanase (encoded by the gene NGLY1) is responsible for cleaving N-linked glycans from misfolded glycoproteins, so that the body can recycle them.

Lacking N-Glycanase leaves the body with an impaired capacity to recycle misfolded glycoproteins, which appear to accumulate in the cells of patients.

The current hypothesis is that accumulation of these misfolded glycoproteins is what causes the harm in these patients.

There are two published papers on N-Glycanase deficiency.

In 2012, Need et al. were the first to discover the disorder by linking the symptoms to mutations in the NGLY1 gene via exome sequencing: 
Need et al. Clinical application of exome sequencing in undiagnosed genetic conditions.Journal of Medical Genetics. June 2012.
In 2014, Enns et al. published a collaborative study of eight NGLY1 patients, identifying characteristic features of the disorder: 
Enns et al. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genetics in Medicine. March 2014.
NGLY1 parents Matt Might and Matt Wilsey co-authored a commentary in Nature's journal,Genetics in Medicine
Matthew Might and Matt Wilsey. The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated. Genetics in Medicine. March 2014.

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