NGLY1 deficiency (or N-glycanase deficiency) is an extremely rare genetic disorder of the endoplasmic reticulum. It falls within the family of Congenital Disorders of Glycosylation (CDG). In this disorder, the cells of the body cannot synthesize the enzyme N-glycanase. N-glycanase 1 (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, and which is 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 broader range of mutations are detected.
N-glycanase deficiency is recessive: when parents are carriers, they have a 25% chance of producing a child with the disorder for each pregnancy.
The list of signs and symptoms mentioned in various sources for NGLY1 includes the symptoms listed below:
- Global developmental delay
- Movement disorder
- 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. Liver values may trend toward the normal range over time.
- A smaller head (microcephaly): Patients tend to have a smaller head circumference, this may be relative to body size and/or acquired over time.
- 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."
- Peripheral neuropathy
NGLY1 deficiency is believed to be caused by a lack of an enzyme called N-glycanase-1, which is encoded by the gene NGLY1.
There is no cure or treatment for N-glycanase deficiency. There is an effort underway to initiate a clinical trial of a new drug that may be highly beneficial for NGLY1 patients.
For individual symptoms, the following treatments have shown benefit in some patients.
Most patients use preservative-free eye drops regularly to moisturize their eyes. For severe dry eyes, patients use sterile petrolatum-based lubricating eye ointment (such as Systane Lubricant) multiple times per day and at night.
If there has been damage to the eye from dryness, a steroid eye ointment like Lotemax may be useful several times per week.
In severe cases, a tarsorrhaphy may be indicated.
Many patients use Miralax and/or fiber supplements (optifiber, psyllium husk or papaya) to relieve constipation.
Epilepsy / Seizures
For patients with seizures, the following medications have proved most effective:
- Valproic acid (Depakote): For reducing seizures (especially myoclonic).
- Lamotragene: For reducing seizures (especially myoclonic).
Most other seizure medications and the ketogenic diet have not yielded significant seizure relief.
N-Acetyl cysteine has been recommended for improving the glutathione response, and it has shown benefits in some patients. The effervescent formulation dissolved in water or a soft food such as apple sauce is recommended.
To alleviate symptoms from possible mitochondrial dysfunction, some patients take coenzyme Q10 (CoQ10) in its ubiquinol form.