NORD gratefully acknowledges Christina Lam, MD, FAAP, FACMG, Assistant Professor, Biochemical Genetics, Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children’s Hospital, and the NGLY1 Foundation, for assistance in the preparation of this report.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. As researchers learn more about the disorder, the potential spectrum or specific pattern of symptoms will be clearer. Therefore, it is important to note that every child is unique and that an individual child may not have all the symptoms discussed below.
Affected infants often have diminished muscle tone (hypotonia), in which the baby is described as excessively “floppy.” About half have a low weight at birth and, despite a normal appetite, many infants will fail to gain weight or grow as would be expected based on their age and gender (failure to thrive). Some infants have difficulty swallowing and are at risk of food or liquids going down the wrong tube and ending up in the lungs (aspiration). Constipation can also occur. In some children, the circumference of the head, which is normal at birth, may be smaller than would be expected as they age (acquired microcephaly).
Affected infants and children may not produce tears or produce few tears when they cry (alacrima). This can lead to complications including inflammation of the eyelids (blepharitis), eye infection, irritation and open sores on the cornea, the transparent layer atop the eye (corneal ulceration). The eyes may not be aligned properly and may point in different directions (strabismus). In a few children, there was degeneration of the main nerve that transmits sensory input to the brain to form images (optic atrophy) and pigment changes in the membrane lining the back of the eyes (retina), and abnormalities of certain cells of the retina called cone cells (cone dystrophy). Vision impairment has been described in some children as well.
Neurodevelopmental symptoms are common in NGLY1 deficiency including delays in reaching developmental milestones like sitting up, crawling, or walking. As they age, children may have difficulty walking independently or be unable to walk. There may be delays in speech development, and children are often unable to speak or can only speak a few words. Intellectual disability is common and can range from children with below average IQ scores to significant intellectual disability.
Affected children may have a complex movement disorder that includes quivering or shaking (tremulousness) and abnormally increased and sometimes uncontrollable muscle spasms (hyperkinesis). Specific movement abnormalities include choreoathetosis, action tremor, myoclonic movements, dystonic movements, and dysmetria. Choreoathetosis is characterized by irregular, rapid, jerky movements that may occur in association with slow, writhing movements. Other types of abnormal movements can develop including a slight tremor when trying to perform a task (action tremor), twitching or jerking (myoclonic movements) movements, involuntary muscle contractions that force the body into abnormal (and sometimes painful) movements or positions (dystonic movements), and a lack of coordination and accuracy in voluntary movements (dysmetria), which means affected individuals will under- or overreach when trying to grab an object, or under- or overstep when walking.
Some children may have elevated levels of certain liver enzymes, which normally indicate liver dysfunction or damage. Mild scarring (fibrosis) of the liver can develop. Most of the time, the liver enzyme levels improve as a child ages. Sometimes, the liver may be larger than normal (hepatomegaly).
Some children have developed seizures of various types. The age of onset for seizures has ranged from two months to 10 years old. Sometimes, the seizures have responded to medications and other times they have continued despite drug therapy (intractable seizures).
A variety of skeletal problems have been reported including small hands or feet, recurrent fractures, a defect of the hip that causes the thigh bone to angle out to the side of the body (coxa valga), abnormal sideways curvature of the spine (scoliosis), joints that are loose and have a larger range of motion than normal (joint hypermobility), and partial (subluxation) or full dislocations of certain joints like the hip or shoulder.
A few affected children have been prone to developing repeated, severe respiratory infections. Most children, however, are no different or have fewer infections than unaffected children.
Some affected individuals develop peripheral neuropathy, a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain. As it progresses, peripheral neuropathy can lead to sores or infections in the feet that don’t heal, weakness, and balance and walking problems.
Some children experience hearing loss. The ears function normally, but the way the brain processes sound is abnormal (auditory neuropathy). Additional symptoms can include an abnormally large spleen (splenomegaly), temporary, recurrent interruptions of breathing during sleep (sleep apnea), a disturbed sleep pattern, diminished reflexes or an inability or reduced ability to sweat; this may make it difficult for affected individuals to regulate body temperature (causing them to overheat) during warm months.
NGLY1 deficiency is caused by a disease causing (pathogenic) variant in the NGLY1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
Researchers have determined that the NGLY1 gene produces a specialized protein (enzyme) called N-glycanase that helps to remove and recycle damaged proteins within the body. This enzyme is involved in a process called deglycosylation, in which sugar molecules called sugar ‘trees’ or glycans are removed from proteins. This step is essential in breaking down damaged or misshaped (misfolded) proteins. Misfolded proteins can become trapped within cells destroying the cell, build up within certain tissues or organs of the body, and damage surrounding tissue or organs. Because of the mutation in the NGLY1 gene, affected individuals do not develop sufficient levels or develop an ineffective form of N-glycanase and cannot properly breakdown and remove damaged proteins from the body. Researchers believe these misfolded proteins buildup in certain tissues of the body. N-glycanase is also be important in regulating some aspects of reading DNA (DNA transcription). The exact manner the deficiency of the N-glycanase protein ultimately causes the symptoms of the disorder is not fully understood yet.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. NGLY1 deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
NGLY1 deficiency is an extremely rare disorder that was first reported in the medical literature in 2012. According to the NGLY1 Foundation, as of January 2018, there are approximately 63 individuals worldwide who have been identified with the disorder. Rare diseases like NGLY1 deficiency often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
A diagnosis of NGLY1 deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. There are no formal diagnostic criteria established for this disorder. A combination of characteristic symptoms including developmental delays, alacrima, hyperkinetic movement disorders, and liver disease may prompt testing for the disorder.
Clinical Testing and Workup
Most individuals are diagnosed through molecular genetic testing. Molecular genetic testing can detect mutations in the NGLY1 gene known to cause NGLY1 deficiency, but is available only as a diagnostic service at specialized laboratories.
If molecular genetic testing identifies variants in the NGLY1 gene that have never been seen before, research is necessary to confirm a diagnosis. Sometimes the research testing needs a small sample of skin tissue that is obtained by cutting off a small piece of skin (excision), which is then studied under a microscope (skin biopsy).
Liver chemistry tests can reveal elevated levels of certain liver enzymes, aspartate transaminase (AST) and alanine transaminase (ALT) in the blood. Sometimes, there is elevation of alpha-fetoprotein (AFP). Elevation of these liver enzymes can occur in a variety of diseases and is not diagnostic of NGLY1 deficiency on their own. Elevated levels of these enzymes and children normalizes with age, and this testing is not effective for older children.
Researchers have discovered that testing the urine of affected individuals may reveal abnormalities of certain long sugar chains called oligosaccharides.
The treatment of NGLY1 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children (pediatric neurologists), neurologists, a physician who specializes in the diagnosis and treatment of disorders of the eye (ophthalmologists), a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract (gastroenterologist), a physician who specializes in the diagnosis and treatment of liver disorders (hepatologist), a physician who specializes in the diagnosis and treatment of skeletal disorders (orthopedist), a physician who specializes in the diagnosis and treatment of genetic disorders (medical geneticist), speech pathologist, psychologist, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with NGLY1 deficiency.
Infants with NGLY1 deficiency should be evaluated for feeding issues and treated with standard methods if necessary. This may include the insertion of a feeding tube. A feeding tube may run through the nose and down the esophagus into the stomach, or may be directly inserted into the stomach through a small surgical opening in the abdominal wall. A feeding tube ensures that affected individuals receive sufficient nutrients.
Poor production or lack of production of tears may be treated with lubricating eye drops or bland ointments. Anti-seizures medications called anti-epileptics may be tried. Sometimes, these medications are effective, but other times the seizures continue (intractable seizures). Braces and other orthotic devices can help children walk. Some children will require a wheelchair.
Individuals with an inability to sweat may require access to water to remain hydrated, especially when involved in physical exertion. Items likes a cooling vest or access to cool environments (e.g. those with air conditioning or other cooling methods) is also beneficial.
Affected children may benefit from occupational, physical, and speech therapy. Water and music therapy have also been beneficial for some affected children. Assistive and augmentative communication devices can help children express thoughts, wants, needs and ideas. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.
Many symptoms associated with NGLY1 deficiency including constipation, scoliosis, sleep apnea, and hearing loss follow standard or routine treatment options.
Researchers are studying proton pump inhibitors as a potential therapy for NGLY1 deficiency. These medications, commonly used to treat gastroesophageal reflux, suppress the production of acid in the stomach. These medications block or reduce (inhibit) the activity of proteins in the body. Proton pump inhibitors block the activity of endo-beta-N-acetylglucosaminidase (ENGase), and it is possible that this may be beneficial in individuals with NGLY1 deficiency. Clinical trials are necessary to determine the long-term safety and effectiveness these medications for individuals with NGLY1 deficiency.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Hall PL, Lam C, Alexander JJ, et al. Urine oligosaccharide screening by MALDI-TOF for the identification of NGLY1 deficiency. Mol Genet Metab. 2018 Mar 20. Epub ahead of print. https://www.ncbi.nlm.nih.gov/pubmed/29550355/
Owings KG, Lowry JB, Bi Y, Might M, Chow CY. Transcriptome and functional analysis in a Drosophila model of NGLY1 deficiency provides insight into therapeutic approaches. Hum Mol Genet. 2018;27:1055-1066. https://www.ncbi.nlm.nih.gov/pubmed/29346549
Lam C, Ferreira C, Krasnewich D, et al. Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation. Genet Med. 2017;19:160-168. https://www.ncbi.nlm.nih.gov/pubmed/27388694
Bi Y, Might M, Vankayalapati H, Kuberan B. Repurposing of proton pump inhibitors as first identified small molecular inhibitors of endo-beta-N-acetylglucosaminidase (ENGase) for the treatment of NGLY1 deficiency, a rare genetic disease. Bioorg Med Chem Lett. 2017;27:2962-2966. https://www.ncbi.nlm.nih.gov/pubmed/28512024
Bosch DGM, Boonstra FN, de Leeuw N, et al. Novel genetic causes for cerebral visual impairment. Eur J Med Genet. 2016;24:660-665. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930090/
Caglayan AO, Comu S, Baranoski JF, et al. NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy. Eur J Med Genet. 2015;58:39-43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804755/
He P, Grotzke JE, Ng BG, et al. A congenital disorder of deglycosylation: biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts. Glycobiology. 2015;25:836-844. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487302/
Enns GM, Shashi V, Bainbridge M, et al. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation (ERAD) pathway. Genet Med. 2014;16:751-758. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243708/
Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49:353-361. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375064/
The NGLY1 Foundation. About NGLY1 deficiency: A handbook for patients, families, and healthcare professionals. 2018. Available at: https://www.ngly1.org/handbook/ Accessed March 29, 2018.
Lam C, Wolfe L, Need A, Shashi V, Enns G. NGLY1-related congenital disorder of deglycosylation. 2018 Feb 8. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Internet. Seattle, WA: University of Washington, Seattle; 1993-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK481554/ Accessed March 10, 2018.
Digitale E. Q&A with Greg Enns, MD, about NGLY1 deficiency, a newly discovered genetic disease. Healthier, Happy Lives Blog. March 20, 2014. Available at: https://healthier.stanfordchildrens.org/en/qa-greg-enns-md-ngly1-deficiency-newly-discovered-genetic-disease/ Accessed March 10, 2018.
Genetics Home Reference. NGLY1-congenital disorder of deglycosylation. August 2017. Available at: https://ghr.nlm.nih.gov/condition/ngly1-congenital-disorder-of-deglycosylation Accessed March 10, 2018.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:615273; Last Update:01/18/2017. Available at: https://omim.org/entry/615273 Accessed March 10, 2018.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100