Aspartylglucosaminuria

Aspartylglucosaminuria

Overview

Aspartylglucosaminuria (AGU) is a rare genetic disorder that affects the body’s ability to break down certain sugars due to a deficiency of the enzyme glycosylasparaginase. Without this enzyme, sugars build up in the body which can cause various health issues, especially affecting brain function. The signs and symptoms of AGU usually become noticeable in childhood and progress over time.

Babies appear normal at birth but during childhood (ages 0 to 12) they may learn slowly, have mild intellectual disabilities, be taller and have a larger head compared to their peers. During puberty and early adolescence (ages 13 to 25), learning difficulties become more severe and some skills may decline. Many adults with this condition have severe intellectual disabilities and may need help with daily tasks, often becoming quieter and, in some people, aggressive if disturbed. Typically, adults with AGU also have shorter stature and smaller heads.

Aspartylglucosaminuria (AGU) is caused by disease causing changes (pathogenic variants) in the AGA gene. Inheritance is autosomal recessive.

Most people affected with AGU are of Finnish descent.

Symptoms

Aspartylglucosaminuria (AGU) is a rare genetic disorder that affects development, cognition and multiple body systems. Symptoms appear in early childhood and progressively worsen with age.2-4

Signs and symptoms, according to age, may include:

Infancy to early childhood (birth to 6 years)

Developmental delays: Babies may seem to develop typically at first but fall behind their peers over time.

First signs appear around 12-15 months including delayed speech and clumsy walking

Growth patterns: Normal birth size but some babies have an early growth spurt, and growth may slow down later

Recurrent infections: Frequent ear and respiratory infections often requiring multiple sets of ear tubes and early tonsil/adenoid removal

Craniofacial features: May not be noticeable at birth but become more distinct with age including a large head (macrocephaly), broad face, thick lips, large tongue and a low, wide nasal bridge

Hernias: Many children develop abdominal (protrusion of intestine or other tissue through a weakness or gap in the abdominal wall) or inguinal (groin) hernias

Sleep issues: Difficulty falling asleep and staying asleep are common.

Childhood to adolescence (7-18 years)

Intellectual disability: Children have mild-to-moderate intellectual disability (intelligence quotient (IQ) is usually 50-70 which indicates mild disability).

Cognitive development typically peaks between the ages of 7-10 followed by a slow decline.

Behavioral changes: Young children are often hyperactive and may be diagnosed with attention deficit/hyperactivity disorder (ADHD).

In adolescence anxiety and restlessness become more prominent.

Neurologic features: Clumsiness, poor balance and coordination difficulties are common.

Some people develop seizures in adolescence (not common).

Musculoskeletal issues: Spinal abnormalities (lordosis, scoliosis, or kyphosis) may develop and worsen over time, sometimes requiring braces or surgery.

Misshapen ribs and thin bones can be seen

Muscle weakness may occur

Facial changes: Coarsening facial features become more noticeable

Features include a short, broad nose, thick lips and puffiness around the eyes (periorbital fullness)

Growth delays: Growth is normal in babies and young children but during puberty, growth often slows down leading to short stature in adults.

Skin problems: Some may develop seborrhea, rosacea, or angiofibromas.

Adulthood (18+ years)

Severe cognitive decline: By adulthood, intellectual disability worsens and progresses to moderate (IQ 35-49) and then to severe/profound intellectual disability (IQ <34) and adults become fully dependent on caregivers.

Psychiatric symptoms: Many adults develop apathy and social withdrawal, and some may have psychotic episodes where they disconnect from reality, often involving hallucinations, delusions and/or disorganized thinking.

Seizures: Up to 28% of adults develop epilepsy.

Progressive physical decline: Joint contractures, arthritis, loss of muscle mass and strength and osteoporosis become more severe and some people develop bursitis, leading to additional pain and mobility issues.

Sleep Disruptions: Adults often have repeated interruptions of sleep throughout the night.

Recurrent infections: Respiratory infections remain a major concern, often leading to premature death in middle adulthood.

Many people have a low blood cell count but usually do not need treatment.

AGU is a progressive disorder with worsening symptoms over time. Life expectancy extends into middle adulthood with proper medical care but affected people require lifelong support due to increasing physical and cognitive impairments.

Causes

Aspartylglucosaminuria (AGU) is caused by disease causing changes (pathogenic variants) in the AGA gene.

The AGA gene has instructions to make (codify) an enzyme called aspartylglucosaminidase. This enzyme is active in lysosomes which are structures inside cells that act as recycling centers. Within lysosomes, the enzyme helps break down complex chains of sugar molecules (oligosaccharides) attached to certain proteins (glycoproteins). Variants in the AGA gene can lead to a shortage of aspartylglucosaminidase in lysosomes. Without enough of this enzyme, glycoproteins cannot be broken down properly and start to build up inside the lysosomes. This buildup disrupts normal cell function and can lead to cell death. Nerve cells in the brain are especially affected, and losing these cells causes many of the symptoms of aspartylglucosaminuria.4-6

Inheritance

Aspartylglucosaminuria is inherited in an autosomal recessive manner.

Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.4

Affected populations

Aspartylglucosaminuria (AGU) is most common in individuals of Finnish descent but has been reported worldwide. In Finland, about 260 people have been reported in the medical literature with AGU and 160 of them are still alive. The condition affects 1 in 3,643 children in eastern Finland. Each year, 1 to 3 children with AGU are born in Finland, resulting in about 1.7 to 5 cases for every 100,000 babies born. Globally, there are around 200 to 300 people living with AGU with about 30 in Sweden and Norway. Most Finnish patients (98%) have AGU due to a specific variant of the AGA gene and about 1 in 50 to 60 Finns carry this gene variant.3,4

Disorders with Similar Symptoms

The following conditions may present similar symptoms as those observed in aspartylglucosaminuria (AGU) and need to be considered by the doctors during the differential diagnosis:4

Salla disease: Salla disease is sialic acid storage disorder. Symptoms include not making good eye contact, shaky eye movements (nystagmus), trouble with balance and coordination (ataxia) and weak muscles (hypotonia). While AGU can cause learning delays, people with Salla disease have more noticeable problems with movement. Other forms of sialic acid storage disorder may present some similarities with AGU but usually AGU tends to progress slower.

Neuronal lipofuscinoses: Unlike AGU which affects thinking and learning, these disorders affect sight.

Northern epilepsy: This disorder is known for causing recurrent seizures which do not commonly happen in AGU. Although both conditions affect the brain, the presence of seizures is a distinguishing feature.

Mucopolysaccharidoses (MPS): MPS causes stiff joints, a large, big head, heart and eye problems and bone changes, while AGU mainly causes learning delays and mild facial changes without major bone or eye problems.

I-cell disease (mucolipidosis II): I-cell disease starts in infancy with severe growth delays, swollen gums, stiff joints and bone problems which are more serious and appear earlier than in AGU.

GM1 and GM2 gangliosidoses: These diseases cause rapid brain decline, seizures, vision loss and a red spot in the eye, while AGU causes slower learning problems without vision loss or seizures.

 Diagnosis

Doctors may suspect AGU in individuals who show a combination of the following signs and symptoms: 3,4

Development and behavior difficulties including delayed development and learning difficulties, mild-to-moderate intellectual disability, neurological issues like seizures, poor balance and coordination problems, behavioral changes, including hyperactivity in young children, anxiety in teens, and apathy in adulthood and disruptive sleep patterns.

Physical and health features such as frequent infections, distinct facial features, skin problems, bone and joint problems, digestive issues and low levels of certain blood cells (neutropenia and thrombocytopenia) which may increase infection risk.

Laboratory tests may include: 3,4

Urine tests that look for elevated levels of aspartyl glucosamine and check the activity of certain enzymes in the urine

Analysis of cells from blood or skin (leukocytes or fibroblasts) to identify vacuoles and large lysosomes

Measurement of enzyme activity to check how well the glycosylasparaginase enzyme works in blood or skin cells

Imaging tests can include: 3,4

Brain MRI that can show changes in the brain’s structure such as shrinkage

X-rays of the chest and spine that can reveal problems like wide ribs and issues with the spine

In addition, a family history of AGU may suggest a risk, but not having a family history does not mean a person cannot have AGU.

Genetic testing identifying variants in the AGA gene can confirm the diagnosis. Tests can also be done on amniotic fluid or tissue samples from the placenta to check for AGU before a baby is born.3,4

Recent studies using advanced imaging techniques have shown changes in how the brain connects in people with AGU. Machine learning methods using MRI data have also been successful in distinguishing people with AGU from healthy people with a low error rate.6

Standard Therapies

Affected people may need to be seen by a team of medical specialists who should work together in a coordinated manner. The team should include neurologists, orthopedists, physical therapists and other healthcare providers.

Regular checkups help track development, manage symptoms and adjust treatments. This includes: 4,5

Developmental and educational assessments at each visit

Seizure monitoring as needed

Annual screening for behavioral and sleep issues

Dental exams every 6 months

Monitoring bone, muscle and joint health

Gastrointestinal and blood health assessments

 Common issues such as seizures, mood swings, ear infections and arthritis are typically treated according to standard medical guidelines. For instance, carbamazepine is frequently prescribed to control seizures.

Behavioral and sleep problems are addressed through behavioral therapy and when necessary, medication. Adults may benefit from therapies like physiotherapy and music therapy.

Ear, nose and throat (ENT) specialists might recommend procedures such as ear tube placement, tonsil removal, or adenoid removal for ear infections.

Bone and joint issues should be monitored and treated by orthopedists who may suggest physical therapy, joint care and osteoporosis management.

Additionally, families can find support through support groups, respite care and social work assistance. Care coordination is essential for managing multiple medical appointments, medications and equipment

Type of Doctor Department : Pediatric Neurologist