Aspartylglucosaminuria, often referred to as AGU, is a rare genetic, autosomal recessive disease that results in an inability of the body to breakdown fats, proteins and sugars. This process is necessary for appropriate mental and physical development.
AGU kids are born healthy and happy. They develop and learn skills normally. As the disease progresses and waste builds up in their body, between the ages of 2 and 5 years, the first signs of the disease start to appear.
Life expectancy is from 25 to 35 years of age. Young adults typically die from infections. Prior to death, AGU causes intellectual disability which progressively worsens in adolescence. Most people with this disorder lose much of the speech they have learned and affected adults usually have only a few words in their vocabulary. Adults with AGU may develop seizures or problems with movement. There is currently no approved treatment for AGU.
Most of the reported AGU cases are found in Finland. As of 2012, there were about 260 reported cases of AGU in Finland, where the total population is about five million. One in 18,500 babies is born with AGU in Finland and 1 in 81 people in Finland are carriers of AGU.
The incidence of AGU outside Finland is unknown. The reports of the documented cases came from different countries around the world and currently account for about 50 described cases.
Aspartylglucosaminuria, often referred to as AGU, is a rare genetic, autosomal recessive disease belonging to a group of lysosomal storage disorders. Lysosomes are cellular compartments that contain enzymes responsible for the final (cellular) breakdown of fats, proteins and sugars. This process is necessary for appropriate mental and physical development.
The basis for the disease presentation is the lack of a cellular enzyme that breaks down long sugars attached to proteins (glucoproteins). These proteins are most abundant in the body tissues and in major organs, such as the liver, spleen, thyroid and brain. When the enzyme is not working or not working properly, the sugars are not broken down in cells, leading to their excess accumulation in the body tissues and increased excretion in urine. The process is gradual, damaging the tissues and organs, progressively destroying cells and leading to eventual death. As the disorder progresses, patients typically become severely mentally and physically handicapped before dying in the third or fourth decade of their lives.
AGU is caused by mutations on the Aspartylglucosamidase (AGA) gene. Most of the reported medical information on AGU is derived from the observation of Finnish patients, which represent one genetic mutation. More than 30 different mutations of the AGA gene have been reported in patients of non-Finnish ancestry with more being discovered every year. Patients with different mutations might have different or milder/more profound signs.
AGU babies look healthy and infancy is normal. Once born, girls may have umbilical and boys inguinal hernias, as well as respiratory infections and periods of diarrhea. Early growth spurts usually occur during the first months of life. Initial symptoms are language/speech delay and clumsiness, which appear between two and five years of age. There may be recurring infections. As the disorder progresses, language skills are affected the most. Children continue to develop until their early twenties, but the learning occurs at a slower rate.
The usual diagnosis for a school age child is ADHD, autistic spectrum disorder and/or language/auditory processing disorders.
Intellectual disability progressively worsens in adolescence. Most people with this disorder lose much of the speech they have learned and affected adults usually have only a few words in their vocabulary. Adults with AGU may develop seizures or problems with movement.
All patients excrete early large amounts of aspartylglucosamine in their urine. Biochemical screening tests are easily done by urine chromatography in certified labs only. Genetic testing can establish the diagnosis.
| Life Period (Years) | Level of Mental Retardation | Speech | Self Help | Motor Skills | Personality | Growth | State of Health |
|---|---|---|---|---|---|---|---|
| 0-2 | Normal | Normal | Normal | Stiffness in hips | A kind and easy baby | Growth spurt +1- +2sd | Normal health |
| 2-6 | Subnormal | Delayed | Normal | Walks clumsily | Well behaved | +1sd | Respiratory, infections, diarrhea |
| 6 – 10 | Mild | Unclear | Able to dress/undress | Can bike | Fussy | 0 – +1sd | Benign subcutaneus tumors |
| 10 – 12 | Mild/ moderate | Clear | Able to do some shopping and move in familiar areas | Can ski, not skate | Kind/stubborn and talkative | Slight and short pubertal growth spurt, early menarche, macroorchidism | Arthritis rheumatoid |
| 12 – 16 | Moderate/severe | Clear | No change | No change | Fond of children, joyful, good mood | Growth ceases | Psychotic periods, epileptic seizures |
| 16 – 20 | Severe/moderate | Soft | No change | No change | Tend to withdraw, fond of parents, not interested in opposite sex | Girls gain weight | Restless sleep/sleep disorder, confusion periods |
| 20 – 25 | Severe | Vocabulary decreases | No change | No more biking or skiing | Calm | Normal weight | Restless sleep / sleep disorder, confusion periods |
| 25 – 35 | Profound | Quiet, answers when asked | Active and passive periods | Can walk without a goal | Inactive, confused | No change | Bursitis, osteoporosis |
| 35 – 45 | Profound | Only a few words | Needs help, can eat self | Legs seem not to respond, poor balance | Sit still for hours, angry when disturbed | Lose weight | Orofacial dystopia |
| 45+ | Profound | No speech | Needs diapers | Wheelchair | Quiet | Malnutrition, underweight | Abcesses, fistula of skin, diarrhea, anemia, psychiatric symptoms, heart insufficiency |
Ritva Tikkanen, PhD, is a professor of biochemistry and molecular biology at the medical faculty of the University of Giessen in Germany. She has been involved in research on AGU for almost thirty years, since starting her Master Thesis in Finland. Dr. Tikkanen shared her perspective with us:
“Patients and families confronted with the diagnosis for a rare disease often face many obstacles like lack of information about the disease, and especially lack of any kind of therapies. There is a tremendous need for novel therapies for rare diseases, including AGU. I have been following the research field for AGU since almost 30 years now, and finally, there is a sparkle of hope for all the AGU patients and their families. I am extremely happy to know that a therapy might soon be available for patients suffering from this devastating disease. I would like to strongly support this important project that will help to save the lives of a number of wonderful kids like Makeda. Every donation, no matter how small, is a further step towards the goal, gene therapy for AGU!”
View the latest research paper on gene therapy for AGU, co-authored by Dr. Tikkanen – Pre-clinical Gene Therapy in AGU.
