What is NGLY1 Deficiency?
A Comprehensive Overview.

NGLY1 Deficiency (pronounced N-gleye-one) is an ultra-rare genetic disorder caused by mutations in the NGLY1  gene that primarily affect a child's cognitive and motor function abilities in early childhood. Although there are no approved therapies, caregivers can treat specific symptoms and use physical therapies to improve their child's quality of life. Since the discovery of NGLY1 Deficiency, the Grace Science Foundation (GSF) has conducted scientific research to understand the disease, and built a world-wide NGLY1 patient community to raise awareness and share resources with affected families.

Disease Overview

NGLY1 Deficiency, sometimes referred to as a congenital disorder of deglycosylation (NGLY1-CDDG), is caused by mutations in both copies of the NGLY1  gene (one from the mother and one from the father) that affect normal function of the NGLY1 protein. Normally, the NGLY1 protein plays an important role in removing cellular waste. When this process is disrupted, this waste buildup causes cellular stress that impacts the body’s normal functioning and leads to disease symptoms.

Click here for a deeper dive into the genetics of NGLY1 Deficiency

What is a Gene?

Genes are like individual instruction manuals for proteins and other components in cells that make up our bodies, directing our cells how to work. Humans have over 20,000 known genes with important roles that range from telling your cells how to digest food and grow into muscle tissue to sending chemical signals in your brain. When a gene is mutated, this may cause written errors in the instruction manual and prevent cells from operating correctly.

NGLY1 Deficiency is an autosomal recessive disorder, which means a child must inherit two mutated NGLY1  genes, one from each parent, to have a positive diagnosis of the disease. Parents of affected children have one normal and one mutated NGLY1  gene and do not have the disease or show symptoms of the disease. They are called carriers.

NGLY1  Gene

The NGLY1  gene provides instructions for making a protein called NGLY1 (short for N-glycanase 1), which plays an important role in breaking down proteins tagged with attached sugars in our cells for their removal (like taking out garbage in a cell). The name N-glycanase 1 can be broken down into “glycan” meaning “sugar molecule”, and “-ase” meaning “to break down,” describing NGLY1’s essential function of removing sugar molecules from other proteins for their disposal within the cell.

When someone has NGLY1 Deficiency, their body is unable to make enough of the NGLY1 protein, leading to cellular waste that is not effectively degraded. This causes a buildup of improperly processed proteins in the body, which can affect different organs and systems, leading to a range of symptoms and potentially shortened life expectancy.

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Individuals with NGLY1 Deficiency are diagnosed through a combination of genetic (DNA) testing and clinical evaluations. Typical symptoms of NGLY1 Deficiency include global developmental delay, low muscle tone, elevated liver enzymes, movement disorders, decreased tear production, and polyneuropathy (nerve damage, specifically in extremities). Caregivers can treat individual symptoms to ease discomfort and use physical therapies to maintain and improve daily skills.

NGLY1 Deficiency is extremely rare, with ~170 confirmed cases around the world as of April 2026. Due to the rarity and limited patient population, more research must be done to comprehensively understand the disease and how it affects patients over time. In many cases patients may lose skills or abilities as they age. People with NGLY1 Deficiency often have a shortened life expectancy. However, because the disease affects everyone differently, it is hard to know exactly how long a specific person will live. The oldest known patient is 43 years old, but there have also been reported patient deaths much younger, with a median age of death at 14 years.

Signs and Symptoms

During pregnancy, a parent might notice less kicking or moving than usual. This is often a first symptom of NGLY1 Deficiency, although it varies from person to person. Many families do not notice symptoms until early childhood (about 4-months old) when their child does not meet expected developmental milestones. For instance, many parents start searching for answers when their child is not sitting up or talking around the same time as their peers.

Children with NGLY1 Deficiency may experience differences in symptoms and have different levels of disease severity. For instance, one child with NGLY1 Deficiency may be higher-functioning (able to speak in short sentences or walk), while another child may be lower-functioning (unable to speak/walk and/or have severe epilepsy). It is not fully understood why these differences occur. Even siblings with the same NGLY1 mutations may have significant differences in disease severity.

Below is a list of the common symptoms identified in NGLY1 Deficiency:

Diagnosis

Like most rare-diseases, the journey to an accurate diagnosis can be long. The average time it takes to receive an NGLY1 Deficiency diagnosis is 6 years. Many patients are undiagnosed or misdiagnosed for years due to its rarity and broad range of symptoms. The Grace Science Foundation is working to raise awareness so that earlier, accurate diagnosis is possible.

A diagnosis of NGLY1 Deficiency can be made through genetic testing that confirms two mutated copies of the NGLY1 gene. Common genetic tests include whole exome sequencing (WES), whole genome sequencing (WGS), or a sequencing panel that includes NGLY1. Ask your doctor for an NGLY1 genetic test if you believe your child may have NGLY1 Deficiency.

If a genetic test cannot determine a diagnosis, a test for the NGLY1 Deficiency biomarker GNA can be used to support a diagnosis. The Grace Science Foundation can help facilitate this test to confirm a diagnosis (contact our email info@gracescience.org for more information).

History

The first case of NGLY1 Deficiency was discovered in 2012. At the time, doctors didn't really know what the diagnosis meant. There was little understood about the NGLY1 gene or how certain changes (mutation) affected the body and caused disease.

As DNA testing became easier for families to pursue, more and more patients were diagnosed. In 2014, the Grace Science Foundation was founded to help families with NGLY1 Deficiency find community and get support. Since then, the Foundation has identified over 170 patients around the world and has funded research to advance the medical field's knowledge of the disease.

Treatment

Currently, there is no approved therapy for the treatment of NGLY1 Deficiency. Instead, caregivers can focus on treating individual symptoms and using physical therapies to help preserve their child's quality of life. Most commonly, physical, occupational, and speech therapy can be utilized to strengthen skills such as gross (e.g., standing and walking) and fine (e.g., holding utensils) motor skills. Many children use augmented and altered communication (AAC) devices to assist with communication, which many parents have found very helpful.

Below are possible symptom treatments and procedures a doctor may recommend:

• Eye drops or eye ointment for dry eyes
• Laxitives for severe constipation
• Anticonvulsant medication for seizures
• Botox injections for severe muscle spasms or hypotonia
• Botox injections to prevent drooling and reduce asphyxiation risk
• Castings for joint contractures (tightening of the muscles, tendons, and ligaments around a joint that limits movement)
• Spinal fusion for severe scoliosis
• Heel cord lengthening surgery for improved mobility
• Feeding tube placement for difficulty feeding