Understanding AGU

Aspartylglucosaminuria (AGU) is a rare, neurodegenerative lysosomal storage disorder (LSD). LSDs are a group of inherited metabolic diseases caused by a genetic variant resulting in a deficiency or absence of a critical enzyme, leading to the accumulation of toxic deposits in cells throughout the body.

AGU is caused by a deficiency or lack of activity in the aspartylglucosaminidase (AGA) enzyme. The deficiency of this enzyme activity leads to toxic deposits in cells, causing cellular dysfunction across multiple organ systems, the most debilitating of which is in the central nervous system, including the brain. Both males and females may be affected.

Signs and symptoms of AGU vary with age. Developmental issues include speech delay, poor motor coordination, difficulty understanding simple instructions, behavioral and emotional issues, and intellectual disability. Other medical issues have been reported such as gastrointestinal disturbances, respiratory infections including recurrent ear infections, and in some cases, seizures in older patients (> age 20). People with AGU have a shortened lifespan.1,2

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AGU was first reported in 1968 in England. AGU cases have been documented throughout the world and across ethnicities, races, heritages, and geographies including North America, Europe, Asia, and the Middle East with the highest known prevalence in Finland.²

Places Reported to Include People Diagnosed with AGU (1975 – 2019):

  1. Lokko, H. N., & Stern, T. A. (2015). Regression: Diagnosis, evaluation, and management. The Primary Care Companion for CNS Disorders, 17(3). Retrieved June 5, 2019, from link.
  2. Arvio, M., & Mononen, I. (2016). Aspartylglycosaminuria: a review. Orphanet Journal of Rare Diseases, 11(162). Retrieved June 5, 2019, from link.

Additional Sources:

  1. Aronson, N. N. (1999). Aspartylglycosaminuria: Biochemistry and molecular biology. Biochimica Et Biophysica Acta, 1455(2-3), 139-154. Retrieved June 5, 2019, from link.
  2. ASPARTYLGLUCOSAMINIDASE; AGA. (2010, January 21). Retrieved June 5, 2019, from link.
  3. Arvio, P., & Arvio, M. (2002). Progressive nature of aspartylglucosaminuria. Acta Paediatrica, 91(3), 255-257. Retrieved June 5, 2019, from link.
  4. Gordon, B. A., Rupar, C. A., Rip, J. W., Haust, M. D., Coulter-Mackie, M. B., Scott, E., & Hinton, G. G. (1998). Aspartylglucosaminuria in a Canadian family. Clinical and Investigative Medicine, 21(3), 114-123. Retrieved June 5, 2019, from link.
  5. Zlotogora, J., Ben-Neriah, Z., Abu-Libdeh, B. Y., Sury, V., & Zeigler, M. (1997). Aspartylglucosaminuria among Palestinian Arabs. Journal of Inherited Metabolic Disease, 20(6), 799-802. Retrieved June 5, 2019, from link.
  6. Chitayat, D., Nakagawa, S., Marion, R. W., Sachs, G. S., Hahm, S. Y., & Goldman, H. S. (1988). Aspartylglucosaminuria in a Puerto Rican family: Additional features of a panethnic disorder. American Journal of Medical Genetics, 31(3), 527-532. Retrieved June 5, 2019, from link.
  7. Hreidarsson, S., Thomas, G. H., Valle, D. L., Stevenson, R. E., Taylor, H., McCarty, J., . . . Green, W. R. (1983). Aspartylglucosaminuria in the United States. Clinical Genetics, 23(6), 427-435. Retrieved June 5, 2019, from link.
  8. Vargas-Díez, E., Chabás, A., Coll, M. J., Sánchez-Pérez, J., García-Díez, A., & Fernández-Herrera, J. M. (2002). Angiokeratoma corporis diffusum in a Spanish patient with aspartylglucosaminuria. British Journal of Dermatology, 147(4), 760-764. Retrieved June 5, 2019, from link.
  9. Laitinen, A., Hietala, M., Haworth, J. C., Schroeder, M. L., Seargeant, L. E., Greenberg, C. R., & Aula, P. (1997). Two novel mutations in a Canadian family with aspartylglucosaminuria and early outcome post bone marrow transplantation. Clinical Genetics, 51(3), 174-178. Retrieved June 5, 2019, from link.
  10. Fisher, K. J., & Aronson, N. N. (1991). Deletion of exon 8 causes glycosylasparaginase deficiency in an African American aspartylglucosaminuria (AGU) patient. FEBS Letters, 288(1-2), 173-178. Retrieved June 5, 2019, from link.
  11. Saarela, J., Von Schantz, C., Peltonen, L., & Jalanko, A. (2004). A novel aspartylglucosaminuria mutation affects translocation of aspartylglucosaminidase. Human Mutation, 24(4), 350-351. Retrieved June 5, 2019, from link.
  12. Labate, A., Barone, R., Gambardella, A., Civitelli, D., Fiumara, A., Annesi, G., . . . Quattrone, A. (2004). Startle epilepsy complicating aspartylglucosaminuria. Brain and Development, 26(2), 130-133. Retrieved June 5, 2019, from link.
  13. Gehler, J., Sewell, A. C., Becker, C., Hartmann, J., & Spranger, J. (1981). Clinical and biochemical delineation of aspartyl-glycosaminuria as observed in two members of an Italian family. Helvetica Paediatrica Acta, 36(2), 179-89. Retrieved June 5, 2019, from link.
  14. Park, H., Vettese, M. B., Fensom, A. H., Fisher, K. J., & Aronson, N. N. (1993). Characterization of three alleles causing aspartylglycosaminuria: Two from a British family and one from an American patient. Biochemical Journal, 190(3), 735-741. Retrieved June 5, 2019, from link.
  15. Guy, R., Forsyth, J. M., Cooper, A., & Morton, R. E. (2001). Co-existence of lysosomal storage diseases in a consanguineous family. Child: Care, Health and Development, 27(2), 173-181. Retrieved June 5, 2019, from link.
  16. Evers, L. J., Schrander-Stumpel, C. T., Engelen, J. J., Mulder, H., Borghgraef, M., & Fryns, J. P. (1993). Terminal deletion of long arm of chromosome 4: Patient report and literature review. Journal of Genetic Counseling, 4(2), 139-145. Retrieved June 5, 2019, from link.
  17. Ziegler, R., Schmidt, H., Sewell, A. C., Weglage, J., Von Lengerke, J. H., & Ullrich, K. (1989). [Aspartylglucosaminuria. Clinical description of 2 German patients]. Monatsschrift Kinderheilkunde, 137(8), 454-457. Retrieved June 5, 2019, from link.
  18. Borud, O., Strömme, J. H., Lie, S. O., & Torp, K. H. (1978). Aspartylglycosaminuria in Northern Norway in eight patients: Clinical heterogeneity and variations with the diet. Journal of Inherited Metabolic Disease, 1(3), 95-97. Retrieved June 5, 2019, from link.
  19. Opladen, T., Ebinger, F., Zschocke, J., Sengupta, D., Ben-Omran, T., Shahbeck, N., . . . Hoffmann, G. F. (2014). Aspartylglucosaminuria: Unusual neonatal presentation in Qatari twins with a novel aspartylglucosaminidase gene mutation and 3 new cases in a Turkish family. Journal of Child Neurology, 29(1), 36-42. Retrieved June 5, 2019, from link.
  20. Musumeci, S., Salvati, A., Schiliró, G., Salvo, G., Di Dio, R., & Caprari, P. (1984). Homozygous NADH-methemoglobin reductase and aspartylglucosaminidase deficiencies in a moderately retarded Sicilian child. American Journal of Medical Genetics, 19(4), 643-650. Retrieved June 5, 2019 from link.
  21. Emre, S., Terzioğlu, M., Coşkun, T., Tokath, A., Ozalp, I., Müller, V., & Hopwood, J. (2002). Biochemical and molecular analysis of mucopolysaccharidoses in Turkey. The Turkish Journal of Pediatrics, 44(1), 13-17. Retrieved June 5, 2019, from link.
  22. Yoshida, K. (1993). Molecular analysis of the aspartylglucosaminidase gene in Japanese patients with aspartylglucosaminuria. Journal of Japan Surgical Association, 51(9), 2308-2313. Retrieved June 5, 2019, from link.

How AGU Affects the Body

AGU affects children both cognitively and physically. Aspects of the disease may include:

Science Behind AGU

The underlying cause of AGU is found in an individual’s chromosomal structure. In humans, each cell contains 23 pairs of chromosomes for a total of 46: 23 from their mother and 23 from their father. The first 22 pairs of chromosomes are called autosomes, and they look the same in both males and females.  The 23rd pair are called sex chromosomes, which are different between males and females. Females have two copies of the X chromosomes (XX), and males have one X and one Y chromosome (XY). A pathogenic variant in a gene on one of the first 22 non-sex chromosomes can lead to an autosomal disorder.

 

 

 

Autosomal recessive describes one of several ways that a disorder or disease is passed down through families. An autosomal recessive disorder occurs when a child inherits two copies of an abnormal gene, one from the mother and one from the father. The biological parents oftentimes have no symptoms of disease because the one functional gene is able to compensate for the defective gene. This means that two healthy people can produce a child or multiple children with the same genetic disorder.

AGU is inherited in an autosomal recessive pattern, meaning both copies of the AGA gene variant (one from each parent) must be present in the person diagnosed with AGU.

 

 

 

 

Healthy AGA Gene

People with AGU have two defective copies of the AGA gene. The AGA gene provides the body with instructions for building the AGA enzyme, aspartylglucosaminidase, which is important in breaking down aspartylglucosamine. When the AGA enzyme is built correctly, aspartylglucosamine is broken down in the lysosomes and waste is recycled or disposed of properly resulting in normal cellular function.

AGU Gene

When there are two defective copies of the AGA gene, the body creates a defective AGA enzyme that cannot perform an essential function of clearing toxic waste from the lysosomes and ultimately leads to cell death. Over time, this accumulated cell death in people with AGU leads to progressive damage in the brain and other organs.

Additional information on the AGA gene can be found here.

 

  1. Lokko, H. N., & Stern, T. A. (2015). Regression: Diagnosis, evaluation, and management. The Primary Care Companion for CNS Disorders, 17(3). Retrieved June 5, 2019, from link.
  2. Arvio, M., & Mononen, I. (2016). Aspartylglycosaminuria: a review. Orphanet Journal of Rare Diseases, 11(162). Retrieved June 5, 2019, from link.

Additional Sources:

  1. Burt, A. D., Ferrell, L. D., & Hübscher, S. G. (Eds.). (2018). Macsween’s Pathology of the Liver (7th Edition). Amsterdam, NL: Elsevier Ltd.
  2. N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase (n.d.). Retrieved June 5, 2019, from link.
  3. AGA Gene. Retrieved June 5, 2019, from link.

Birth Through
Age 5

Children experience developmental delays. Common signs and symptoms include:

  • Delayed speech
  • Sleep disturbance
  • Chronic ear infections, often requiring multiple ear tube placements
  • Frequent upper respiratory infections often resulting in tonsillectomy
  • Delay in sitting up
  • Clumsy walking
Birth Through<br />Age 5

Our daughter struggled with orthopedic challenges. She was continuously falling and was unable to brace herself when she fell. We added supportive soles to her shoes that went ankle high. Her kindergarten teachers also indicated that she was learning slower than her classmates.

- Eeva, mother living in Finland reflecting on her daughter’s younger years living with AGU

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Adolescent Years

As the disease continues to progress through the adolescent years, other signs and symptoms may become apparent:

  • Intellectual disability will progressively worsen
  • Sleep disturbance
  • Anxiety, restlessness, and inability to understand the concept of time
  • Emotional, behavioral, and psychiatric issues can arise
  • Dental complications such as tooth decay, large tongue, and enlarged tonsils
  • Progressive thickening of facial features: widely-spaced eyes, small ears, full lips, large tongue, broad nose
  • Gastrointestinal symptoms including diarrhea or constipation
  • Gait (walking) disturbance
Adolescent Years

Childhood Years

The most common sign of AGU is the lack or delay of speech. In addition, other signs and symptoms that become apparent in AGU children throughout the elementary school-age years include:

  • Speech delay: support needed for missing words or letters
  • Sleep disturbance
  • Inability to learn shapes or trace figures
  • Inability to follow simple directions and trouble managing daily tasks
  • Thickening of facial features: widely-spaced eyes, small ears, full lips, large tongue, broad nose
  • Upper respiratory infections, specifically ear infections
  • Hernias around the belly button or in the groin area
  • Gastrointestinal symptoms including diarrhea or constipation
  • Orthopedic challenges, which may require surgery, including rolling instep, toe walking, knock knees, or spastic running
Childhood Years

Our son is extremely social and makes friends easily; however he becomes easily distracted, especially by the TV, or he can become very restless if there are not people there to keep his motivation levels up. Sometimes, he struggles with conflict resolution and gets more frustrated than others in certain situations.

- Mika, father of son living with AGU in Sweden

Read Story

Adulthood

People in their 20s and 30s may lack self-care skills and independence. Common signs and symptoms during this time include:

  • Seizures
  • Acceleration of cognitive decline
  • Sleep disturbance
  • Continued regression of previously mastered skills to the point of loss of ability
  • Gait (walking) disturbance
  • AGU-specific facial features become more apparent for example: widely-spaced eyes, small ears, full lips, large tongue, broad nose
Adulthood

Common Signs & Symptoms

While the signs and symptoms of AGU can vary and progress at each stage of a child’s life, there are some common signs and symptoms that are consistent across many cases of AGU.

  • Delay in speech
  • Speech disturbance
  • Characteristic facial appearance (widely spaced eyes, small ears, full lips, broad nose, coarsening of hair)
  • Slow learning of language and simple concepts
  • Problems with motor skills
  • Frequent ear infections, often requiring multiple ear tubes
  • Frequent upper respiratory infections
  • Diarrhea or constipation
  • Hernias (umbilical/belly button and inguinal/inner groin)
  • Clumsy walking (gait issues)
AGU Glossary of Terms
  1. Lokko, H. N., & Stern, T. A. (2015). Regression: Diagnosis, evaluation, and management. The Primary Care Companion for CNS Disorders, 17(3). Retrieved June 5, 2019, from link.
  2. Arvio, M., & Mononen, I. (2016). Aspartylglycosaminuria: a review. Orphanet Journal of Rare Diseases, 11(162). Retrieved June 5, 2019, from link.

Additional Source:

  1. Field research conducted by Neurogene and Ten Bridge Communications, February 2019.

Obtaining a definitive genetic diagnosis is an important first step in seeking appropriate care and treatment, learning about potential research or therapies that may become available, and preparing for the future. Patients and their families should consider discussing the implications of obtaining a diagnosis of AGU with their physician and a genetic counselor or other specialists who are familiar with the disease management of AGU.

Similar to other neurological conditions, developmental delay is an early observed symptom of AGU. As such, common misdiagnoses for AGU may include autism and attention deficit hyperactivity disorder (ADHD) as awareness of AGU is very low.3

 

If you believe your child is showing signs or symptoms of AGU, tests are available for a physician or other healthcare professional to order to help confirm a diagnosis.4,5,6

Testing for AGU may not be included in standard testing panels; however, upon request, a diagnostic genetic test for AGU can confirm a diagnosis. Your physician can help you navigate the process or refer you to a geneticist. Many academic and commercial laboratories offer genetic blood testing.

You may also learn more about a no-charge genetic testing and counseling program by downloading information using the button below.

Download info

For additional details about a no-charge genetic testing and counseling program, click here. To order the genetic test, physicians can download the requisition form here.

While third parties and commercial organizations may provide financial support for this program, tests and services are performed by Invitae. Healthcare professionals must confirm that patients meet certain criteria to use the program. Third parties and commercial organizations may receive de-identified patient data from this program, but at no time would they receive patient identifiable information. Third parties and commercial organizations may receive contact information for healthcare professionals who use this program. Genetic testing and counseling are available in the US and Canada. Healthcare professionals and patients who participate in this program have no obligation to recommend, purchase, order, prescribe, promote, administer, use or support any other products or services from Invitae or from third parties or commercial organizations.

A representative is available to help you by calling 1-877-237-5020 or via email at medicalinfo@neurogene.com.

  1. Lokko, H. N., & Stern, T. A. (2015). Regression: Diagnosis, evaluation, and management. The Primary Care Companion for CNS Disorders, 17(3). Retrieved June 5, 2019, from link.
  2. Arvio, M., & Mononen, I. (2016). Aspartylglycosaminuria: a review. Orphanet Journal of Rare Diseases, 11(162). Retrieved June 5, 2019, from link.
  3. Malm, G., Mansson, J., Winiarski, J., Mosskin, M., & Ringden, O. (2004). Five-year follow-up of two siblings with aspartylglucosaminuria undergoing allogeneic stem-cell transplantation from unrelated donors. Transplantation, 78(3): 415-419.
  4. Xia, B., Asif, G., Arthur, L., Pervaiz, M. A., Li, X., Liu, R., Cummings, R. D., & He, M. (2013). Oligosaccharide Analysis in Urine by MALDI-TOF Mass Spectrometry for the Diagnosis of Lysosomal Storage Diseases. Clin Chem, 59(9):1357-1368. Retrieved June 12, 2019, from link.
  5. Mononen, I., Mononen, T., Ylikangas, P., Kaartinen, V., & Savolainen, K. (1994). Enzymatic diagnosis of aspartylglycosaminuria by fluorometric assay of glycosylasparaginase in serum, plasma, or lymphocytes. Clin Chem, 40(3):385-8. Retrieved June 12, 2019, from link.
  6. Romppanen, E. L., & Mononen, I. (1999). PCR-Oligonucleotide Ligation Assay from Dried Blood Spots. Clin Chem, 45(11):2022-2023. Retrieved June 12, 2019, from link.

While there is currently no cure for people living with AGU, there are a number of specialists today with expertise who can help you manage this disease and its symptoms.

People living with AGU benefit from having a team of healthcare professionals to help manage the progressive impact of their disease. The daily needs of an individual with AGU can be supported by some or all of the following healthcare providers. These needs may change or evolve as a child moves into adulthood.

Click on each circle below for more information about the role each healthcare provider may play to support the daily needs of an individual living with AGU:

In addition to the care team that can help to manage the various symptoms associated with AGU, people living with AGU may also find support through social and educational plans. These plans can help cultivate independent living skills as a person gets older and their symptoms progress.

Discover more resources

 

  1. Lokko, H. N., & Stern, T. A. (2015). Regression: Diagnosis, evaluation, and management. The Primary Care Companion for CNS Disorders, 17(3). Retrieved June 5, 2019, from link.
  2. Arvio, M., & Mononen, I. (2016). Aspartylglycosaminuria: a review. Orphanet Journal of Rare Diseases, 11(162). Retrieved June 5, 2019, from link.