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Aspartylglucosaminuria

This is part of Rare diseases.

Diagnosis: Aspartylglucosaminuria

Synonyms: AGU


Date of publication: 2011-03-16
Version: 1.2

ICD 10 code

E77.1

The disease

Aspartylglucosaminuria (AGU) is a congenital disorder belonging to the category lysosomal diseases. Lysosomal diseases are characterised by an abnormality in lysosomal function, caused by impaired activity in either an enzyme or in a protein transporting materials into and out of the lysosomes. The disease was described for the first time in 1967 by F.A. Jenner and R.J. Pollitt.

To date approximately seventy different lysosomal diseases have been identified. Examples include: cystosis, Danon disease,Fabry disease, Gaucher disease, GM2 gangliosidosis, Krabbe disease, mannosidosis, metachromatic leukodystrophy, mucopolysaccharidoses I, II, III, IV, VI and VII, Pompe disease and Salla disease. Separate information on these diseases can be found in the Swedish National Board of Health and Welfare database of rare diseases.

Occurrence

There are no exact figures of the incidence of the disease in Sweden, but it is estimated that there are at least ten children and adults with aspartylglucosaminuria. The disease is more common in Finland where over 200 individuals have been diagnosed.

Cause

Aspartylglucosaminuria is caused by a mutation in the gene which controls the production of (codes for) the enzyme aspartylglucosaminidase. The gene for this enzyme is located on chromosome 4. In Finland, the same genetic mutation is found in almost every individual with the disease, while in other countries a larger variety of mutations are present.

Lysosomes are small units found in all the cells of the body except red blood cells. With the help of enzymes (a sort of protein) the role of lysosomes is to interact with, and break down, different substances. In this process the constituent parts of the materials are released and become available for re-use. In this way proteins, for example, are broken down into amino acids. These newly-released “building blocks” are then transported out of the lysosomes and become available to cells for the production of new substances.

Aspartylglucosaminidase normally breaks down proteins which contain carbohydrates (glycoproteins). These are plentiful in the tissues of the body, particularly in the cells and cell surfaces of the liver, spleen, thyroid and nerves. When glycoproteins cannot be broken down in the usual way, residues of aspartylglycosaminase and certain other substances accumulate in the lysosomes. These residues cause progressive damage to tissues and organs, manifesting in symptoms of aspartylglucosaminuria.

Heredity

The inheritance pattern of aspartylglucosaminuria is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

Symptoms

Children often show no symptoms at birth. During the first year of life inguinal (groin) and umbilical hernias are common. Enlargement of the liver and spleen may occur, neither of which usually gives rise to serious symptoms. Some children also suffer from diarrhoea.

During early childhood recurrent infections of the ear and upper respiratory system are common.

Initially, motor development is normal. The first signs of impaired development usually manifest in the child’s early years. The child is physically uncoordinated and speech and language development are delayed. Coordination remains poor, but with support and help most individuals can manage everyday activities and participate in play and sporting activities until they reach adulthood.

One characteristic of the disease is a progressive slowing of intellectual development. During their first years children develop normally, but before school age concentration problems, as well as delayed language and intellectual development, become apparent. Development continues, but is slower than normal. Young people in their mid-teens are at their intellectual peak, at which time they can be assessed as having mild to moderate intellectual disabilities. After this age teenagers either remain at this developmental stage or deteriorate slightly until they are between 25 and 30 years of age. After this age learned skills are lost at an increasing rate, resulting in severe learning disability. At the same time, motor skills deteriorate. People with the disease become successively less mobile and more dependant on help and support from those around them. Eventually they will need a wheelchair. However, it should be remembered that there are wide variations both in individuals’ levels of intellectual development and in the progression of the disease.

The average height of people with aspartylglucosaminuria is somewhat lower than the rest of the population. The reason may be the early onset of puberty, which is common among those with the disease.

There may also be minor changes to the skeleton, visible in X-rays. These include changes to the vertebrae. Such changes may cause curvature of the spine (scoliosis) or the bones of the foot.

Many children with aspartylglucosaminuria have similar facial features including a large head, broad lower jaw, a short, broad nose and round cheeks. These characteristic features become more pronounced during the teens. At this age severe acne and/or small red papules (angiofibromas) may appear on the face. Some teenagers with the condition may also develop a hoarse voice. The eyes of some individuals are sensitive to sunlight.

During their childhood and school years, young people with aspartylglucosaminuria are regarded as calm and quiet. Young people with the condition are often active, but when they are older they may become noticeably stubborn, irritable and passive. Sometimes they suffer from depression.

More than half the adults with the condition have epilepsy and younger people are also sometimes affected. Adults with aspartylglucosaminuria often experience insomnia.

Studies in Finland show that life expectancy is shorter than average.

Diagnosis

A diagnosis is made with the help of a urine test, which will establish an increased secretion of aspartylglucosamin. To confirm the diagnosis a blood test is taken. This will indicate that the enzyme aspartylglucosaminidase is wholly or partially absent.

A DNA analysis will establish the mutation which causes the enzyme deficiency. Pre-natal diagnosis is possible.

Treatment/interventions

There is no treatment which will cure the disease or delay its progression. As in other lysosomal disease, attempts have been made to replace the missing enzyme by a bone marrow transplant (hematopoietic stem cell transplantation) so that the transplanted bone marrow produces the missing enzyme. About ten transplants have been carried out in Finland and a few in the rest of the world but as yet results have been inconclusive.

As repeated ear infections of the middle ear can damage hearing it is important that hearing is checked regularly. Susceptibility to infection usually passes after the age of six or seven.

Over-sensitivity to sunlight, particularly in summertime, can be a major practical problem. Sunglasses, hats or caps may be used to protect the eyes.

In cases of severe acne a dermatologist can give advice and treatment.

Epilepsy is treated with medication. Older teenagers or adults may sometimes require medication to counteract anxiety or insomnia. Children with aspartylglucosaminuria who suffer from insomnia have been treated successfully with melatonin medication.If psychiatric problems such as depression become severe, medication can be prescribed.

Children with aspartylglucosaminuria require special teaching at school. When intellectual disability has been confirmed the child benefits from teaching at a special school.

The habilitation of children and young people with aspartylglucosaminuria needs to be started early. A habilitation team includes professionals with special expertise on disabilities and how they affect everyday life, health and development. Support and treatment are provided within the medical, educational, psychological, social and technical fields. Measures may include assessments, treatment, assistance with choice of aids and information about disabilities and counselling. Information about support offered by the local authority, as well as advice on the way accommodation and other environments can be adapted to the child’s needs, is also available. Parents and siblings and other relatives may also receive support.

Habilitation focuses on the needs of the individual. However, needs will change over time as the disease progresses and the child grows.

Local authorities can offer different forms of support to ease everyday life for the family.

These may include respite care and the services of a contact family and/or a care assistant.

In adulthood, medication, habilitation and daily support remain necessary. Care may include support and help in an assisted living facility with round-the-clock care.

Practical advice

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National and regional resources in Sweden

Paediatricians and paediatric neurologists at district and regional hospitals make a diagnosis with the help of laboratory tests.

Two Swedish laboratories specialising in metabolic diseases have resources for making clinical chemical diagnoses:

Department of Clinical Chemistry and Neurochemistry, Sahlgrenska University Hospital/Mölndal, SE-431 80 Mölndal, Sweden.

Centre for Inherited Metabolic Diseases (CMMS), Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden.

Resource personnel

Associate professor Maria Arvio, Paediatric neurology, Päijat-Häme Central Hospital, Lahti, Finland. Email: maria.arvio@phsotey.fi.

Associate Professor Niklas Darin, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Associate Professor Ulrika von Döbeln, The Centre for Inherited Metabolic Diseases (CMMS), Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Associate Professor Gunilla Malm, Department of Paediatrics, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

Associate Professor Jan-Erik Månsson, Department of Clinical Chemistry and Neurochemistry, Sahlgrenska University Hospital/Mölndal, SE-431 80 Mölndal, Sweden. Tel: +46 31 343 10 00.

Senior physician Karin Naess, Paediatric Neurology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

Professor Paul Uvebrant, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Courses, exchanges of experience, recreation

Ågrenska is a national competence centre for rare diseases.

The centre arranges stays for children and young people with rare diseases and their families.

A number of programmes are also provided every year for adults with rare diseases.

Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Organizations for the disabled/patient associations

There is no association for aspartylglucosaminuria in Sweden, but there is a contact family:

Lena Strandell Nyström and Niklas Nyström, Alpvägen 20, SE-150 21 Mölnbo, Sweden. Tel: +46 158 600 23.

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Gävlegatan 18 C, Stockholm, Sweden. Mailing address: Box 6436, SE-113 82 Stockholm, Sweden. Tel: +46ÿ 8ÿ 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

Courses, exchanges of experience for personnel

During family visits to Ågrenska there are also training courses for personnel working with the children and young people participating.

Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Research and development (R&D)

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Information material

An information leaflet on aspartylglucosaminuria that summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2010-5-29). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

The Ågrenska National Competence Centre for Rare Diseases has published a newsletter on aspartylglucosaminuria, nr. 377, 2010 (in Swedish only). The newsletter contains adapted summaries of lectures given at Ågrenska family stays or adult programmes. Order from: Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. The newsletter can also be downloaded from their website: www.agrenska.se.

Literature

Arvio P, Arvio M. Progressive nature of aspartylglucosaminuria. Acta Paediatr 2002; 91: 255-257.

Arvio MA, Rapola JM, Pelkonen PM. Chronic arthritis in patients with aspartylglucosaminuria. J Rheumatol 1998; 25: 1131-1134.

Arvio M. Follow-up in patients with aspartylglucosaminuria. Part I. The course of intellectual functions. Acta Paediatr 1993; 82: 469-471.

Arvio M, Oksanen V, Autio S, Gaily E, Sanio K. Epileptic seizures in aspartylglucosaminuria: a common disorder. Acta Neurol Scand 1993; 87: 342-344.

Arvio M. Follow-up in patients with aspartylglucosaminuria. Part II. Acta Paediatr 1993; 82: 590-594.

Autti T, Lönnqvist T, Joensuu R. Bilateral pulvinar signal intensity decrease on T2-weighted images in patients with aspartylglucosaminuria. Acta Radiol 2008; 49: 687-692.

Dunder U, Valtonen P, Kelo E, Mononen I, Early initiation of enzyme replacement therapy improves metabolic correction in the brain tissue of aspartylglucosaminuria mice. J Inherit Metab Dis 2010;33:611-617.

Ikonen E, Aula P, Grön K, Tollersrud O, Halila R, Manninen T et al. Spectrum of mutations in aspartylglycosaminuria. Proc Natl Acad Sci U S A 1991; 88: 11222-11226.

Ikonen E, Peltonen L. Mutations causing aspartylglucosaminuria (AGU): a lysosomal accumulation disease. Hum Mutat 1992; 1: 361-365.

Lindblom N, Kivinen S, Heiskala H, Laakso ML, Kaski M. Sleep disturbances in aspartylglucosaminuria (AGU): a questionnaire study. J Inherit Metab Dis 2006; 29: 637-646.

Malm G, Månsson JE, Winiarski J, Mosskin M, Ringdén O. Five-year follow-up of two siblings with aspartylglucosaminuria undergoing allogeneic stem-cell transplantation from unrelated donors. Transplantation 2004; 78: 415-419.

Malm G, von Döbeln U, Naess K, Ringdén O. Lysosomala sjukdomar -forskning och framsteg ger hopp om bot och bättring. Läkartidningen 2008; 105: 3731-3735.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: aspartylglycosaminuria

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Gunilla Malm, Karolinska University Hospital, Stockholm, Sweden.

An expert group on rare diseases, affiliated with the University of Gothenburg , approved the material prior to publication.

Date of publication: 2011-03-16
Version: 1.2
Publication date of the Swedish version: 2010-07-01

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.