NGLY1 deficiency is a very rare

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

caused by biallelic pathogenic

variants Variant may refer to: In arts and entertainment * ''Variant'' (magazine), a former British cultural magazine * Variant cover, an issue of comic books with varying cover art * ''Variant'' (novel), a novel by Robison Wells * " The Variant", 2021 e ...

in ''

NGLY1 PNGase also known as N-glycanase 1 (EC 3.5.1.52) or peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase is an enzyme that in humans is encoded by the NGLY1 gene. PNGase is a de-''N''-glycosylating enzyme that removes ''N-''linked or aspar ...

''. It is an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

disorder. Errors in deglycosylation are responsible for the symptoms of this condition. Clinically, most affected individuals display developmental delay, lack of tears, elevated liver transaminases and a movement disorder. NGLY1 deficiency is difficult to diagnose, and most individuals have been identified by

exome The exome is composed of all of the exons within the genome, the sequences which, when transcribed, remain within the mature RNA after introns are removed by RNA splicing. This includes untranslated regions of messenger RNA (mRNA), and coding r ...

sequencing. NGLY1 deficiency causes a dysfunction in the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

-associated degradation pathway. ''NGLY1'' encodes an enzyme, N-glycanase 1, that cleaves N-glycans. Without N-glycanase, N-glycosylated proteins that are misfolded in the endoplasmic reticulum cannot be degraded, and thus accumulate in the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

of cells.

Signs and symptoms

Four common findings have been identified in a majority of patients: developmental delay or intellectual disability of varying degrees, lack of or greatly reduced tears, elevated liver transaminases, and a complex movement disorder. The elevated liver enzymes often resolve in childhood. In addition, approximately 50% of patients described with NGLY1 deficiency have seizures, which can vary in their difficulty to control. Other symptoms that have been reported in affected individuals include

sleep apnea Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many times ...

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...

, oral motor defects, auditory neuropathy and peripheral neuropathy.

Diagnosis

NGLY1 deficiency can be suspected based on clinical findings, however confirmation of the diagnosis requires the identification of biallelic pathogenic variants in ''NGLY1'' through genetic testing. Traditional screening tests utilized for congenital disorders of glycosylation, including carbohydrate deficient

transferrin Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encode ...

are not diagnostic in NGLY1 deficiency. To date all variants identified as being causative of NGLY1 deficiency have been sequence variants, rather than copy number variants. This spectrum may change as additional cases are identified. A common nonsense variant (c.1201A>T (p.Arg401Ter)) accounts for approximately a third of pathogenic variants identified, and is associated with a more severe clinical course. There is also a biomarker for NGLY1 deficiency. When the NGLY1 protein is missing or not functioning correctly, a specific molecule called GlcNAc-Asn (GNA) accumulates. GNA is elevated in individuals with NGLY1 deficiency compared to individuals without the disease. Elevated GNA alone is not enough to confirm an NGLY1 deficiency diagnosis, but in combination with molecular genetic testing and clinical findings, it can provides additional support for NGLY1 deficiency.

Treatment

There is no cure for NGLY1 deficiency. Supportive care is indicated for each patient based on their specific symptoms, and can include eye drops to manage the

alacrima Alacrima refers to an abnormality in tear production that could mean reduced tear production or absent tear production. Because a lack of tears presents in only in a few rare disorders, it aids in diagnosis of these disorders, including Triple-A ...

, pharmaceutical management of seizures, feeding therapy and physical therapy. Most potential treatment options for NGLY1 deficiency are in the pre-clinical stages. These include enzyme replacement therapy, as well as ENGase inhibitors. Efforts are also underway to find small-molecule stabilizers for the mutant NGLY1 protein variants as a potential means to overcome the N-glycanase deficiency.

Epidemiology

Forty-seven patients with confirmed NGLY1 deficiency have been reported in the medical literature. Patient advocacy groups have reported approximately 100 patients have been identified. Currently, the majority of individuals reported with NGLY1 deficiency are of northern European descent, however this likely reflects an ascertainment bias in these early stages of the disorder. Affected individuals with African and Hispanic backgrounds have been identified.

History

The first cases of NGLY1 deficiency were described in 2012. NGLY1 deficiency has received a large amount of attention, despite its rarity, due to the children of two media-savvy families being afflicted. The Wilseys, descendants of

Dede Wilsey Diane Buchanan "Dede" Wilsey is a San Francisco socialite, Republican Party donor, and philanthropist. She is the widow and heir of the San Francisco dairy and real estate businessman Al Wilsey, and the Chair Emerita of the Fine Arts Museums of ...

, founded the Grace Science Foundation in honor of their daughter, while Matt Might and his wife founded the Bertrand Might Research Fund. These foundations have contributed millions of dollars to research efforts.

References

External links

{{Medical resources , ICD10 = {{ICD10, E77.8 , ICD9 = , ICDO = , OMIM = 615273 , DiseasesDB = 36670 , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeSH = , GeneReviewsNBK = 481554 , GeneReviewsName = NGLY1 deficiency , Orphanet = 404454 Genetic diseases and disorders Rare diseases Autosomal recessive disorders Congenital disorders of glycosylation