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Glutaric aciduria type 1

This is part of Rare diseases.

Diagnosis: Glutaric aciduria type 1

Synonyms: Glutaric acidaemia type 1, Glutaryl-coenzyme A dehydrogenase deficiency


Date of publication: 2012-06-19
Version: 1.1

The disease

Glutaric aciduria type 1 is a hereditary, congenital metabolic disease. It is caused by an enzyme deficiency in which certain amino acids are not broken down in the normal way. This deficiency negatively affects the functioning of the brain. It can lead to injury, primarily to the basal ganglia (large centres of nerve cells) in the brain, where nerve cells are injured or destroyed but are not replaced. Long extensions of the nerve cells (neurons) forming the white substance of the brain also sustain some damage. The basal ganglia act as a control centre for, among other things, physical coordination.

In 1975, glutaric aciduria type 1 was described for the first time by American physician Steve Goodman and his colleagues. They established that children with the disease excreted glutaric acid in their urine. Subsequently, the defective enzyme and the mutated gene causing the disease were identified.

Occurrence

It is unclear how common the disease is, but it is estimated that one child in every 100,000 is born with glutaric aciduria, with significant variations between different populations. The disease is found all over the world, but is more common among the Amish people of the US, the Lake Island Indians in Canada and a group of Romany people in Ireland. In Sweden, Norway, Denmark and Finland a total of approximately 40 individuals have been diagnosed with the condition. It is probable that there are currently a number of people with the disease who have not been diagnosed; they may not have developed symptoms or may have become ill as children and developed disabilities.

Cause

The cause of the disease is a mutation in a gene which controls the production of (codes for) the enzyme glutaryl-CoA dehydrogenase. Gene GCDH is located on the short arm of chromosome 19 (19p13.2).

Many different mutations have been described. All of them result in the production of an abnormal enzyme with varying degrees of impaired functionality. This enzyme is involved in mitochondrial function, which supplies energy for nerve cells. (The mitochondrion is a small, energy-producing structure present in all the cells of the body.) A glutaryl-CoA dehydrogenase deficiency results in the amino acids lysine, hydroxylysine and tryptophan being broken down much more slowly than normal. This causes the formation of excessive quantities of glutaric acid, which is excreted in the urine in widely varying amounts. Along with glutaric acid, carnitine is also excreted. Carnitine is an important substance in cell metabolism, playing a role in the breaking down of fatty acids. Everyone with glutaric aciduria develops carnitine deficiency at an early stage of the disease.

Sometimes residual enzyme activity is so high that the presence of glutaric acid cannot be established in the urine.This can make it difficult to make a diagnosis. The exception is when the metabolism is subject to particular strain, during severe infections for example.

Heredity

The inheritance pattern of glutaric aciduria type 1 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

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Symptoms

Of those people with a double set of the mutated gene, between 90 and 95 per cent develop symptoms. The severity of symptoms varies greatly between individuals and ranges from mild to severe neurological disability. In its mildest form the disease may manifest in coordination and concentration problems, or in an unusually large head. Approximately one third of people with the disease develop a mild motor impairment in the form of coordination problems and involuntary movements (choreoathetosis). Approximately two thirds of children develop involuntary, prolonged muscle spasms resulting in recurring, writhing movements and abnormal posture (dystonia), which in turn lead to severe motor disability.

In general, between the age of six and ten months, the child develops normally. In the most common form of the disease the child becomes ill at some time during the first two years, usually in association with a simple infection such as a cold or stomach upset. This illness triggers a crisis in the body’s production of energy (a metabolic crisis). The child experiences circulatory shock and develops severe neurological symptoms including muscle contractions, vomiting and unconsciousness. The condition may be life-threatening, and there is a severe risk of brain damage. It is presumed that these acute conditions are associated with sensitive nerve cells suffering a sudden, serious energy deficiency, resulting in brain damage. The severity of damage varies between children, but it is usually permanent. In severe cases, it causes severe dystonia and motor impairments which include the muscles of mouth and throat. Problems in chewing and swallowing cause major feeding and eating problems and can lead to weight loss.

A less common presentation is when the disease develops gradually over several years during which time the neurological symptoms gradually increase, often manifesting as involuntary and uncoordinated movements (choreoathetosis). There are also individuals with the disease who are asymptomatic and appear not to experience problems until adulthood. Some adults have become ill with completely different symptoms, and were subsequently shown to have damage to the white substance of the brain.

Neurological damage is often associated with an impaired ability to communicate by speech and by handwriting. The severe forms of the disease are associated with an inability to speak. However, people with the disease understand the spoken language well. Involuntary movements and problems with posture can cause difficulties in communication and concentration, but intellectual function is usually not affected as severely as motor skills, and sometimes not at all.

During the first one or two years of life, the heads of many children may grow abnormally quickly, leading to an incorrect suspicion of elevated intercranial pressure (hydrocephalus).

Curvature of the spine (scoliosis) may present gradually.

Following up people with glutaric aciduria type 1 over the long term confirms the opinion that, after the first period of illness, further neurological damage is uncommon.

Diagnosis

An unexpected and dramatic deterioration in a baby’s or child’s general condition when suffering from a simple infection may indicate the presence of the disease. Symptoms of glutaric aciduria type 1 may be confused with other common diseases. On several occasions, glutaric aciduria has been mistaken for acute inflammation of the brain (encephalitis). As children with glutaric aciduria type 1 often have a non-progressive disability, symptoms have sometimes been misinterpreted as indicating cerebral palsy as a consequence of encephalitis.

Examinations of the brain using computed tomography (CAT scan), or magnetic resonance imaging (MRI scan), often show a characteristic picture with both temporal lobes of the brain containing cysts or fluid-filled hollow areas. These cysts have often been wrongly assumed to be the consequences of brain haemorrhages, an assumption resulting in unnecessary operations or even investigations into suspected child abuse. Changes to the eyes, typical of glutaric aciduria, may also be misinterpreted in the same way.

A diagnosis can be confirmed by repeated tests for organic acids in the urine (levels of glutaric acid and 3-OH-glutaric acid can vary) and for carnitine in blood and urine. White blood cells or skin cells are tested for enzyme activity (glutaryl-CoA dehydrogenase).When a child has an infection, does not receive adequate nutrition or has a gastrointestinal illness such as gastroenteritis, these levels rise and it becomes possible to make a firm diagnosis.

Since 2010, glutaric aciduria type 1 has been one of the diseases which can be diagnosed in the general screening of neonates for inherited metabolic disorders (using the PKU test procedure). It is too early to say how effective this diagnostic technique has proved in Sweden, but it should be possible to identify more children with the disease before they present with symptoms.

DNA-based confirmation of the diagnosis is possible.

At the same time that the diagnosis is made the family should be offered genetic counselling. As individuals with the disease do not always develop symptoms, all siblings should be examined. If the genetic mutation causing the disease has been identified, DNA testing of siblings can be carried out. Both pre-natal and embryo diagnosis are possible.

Treatment/interventions

There is currently no cure for this disease. Treatment is directed at preventing acute metabolic crises, alleviating symptoms and organ damage as well as helping to compensate for disabilities and providing support and care. It is extremely important that the disease is discovered at an early stage. Children who have received the correct treatment from birth have developed normally.

As they grow, children and young people with glutaric aciduria type 1 require contact with many different specialists. It is important that monitoring and treatment are coordinated by a paediatrician who has an overview of the child’s condition.

If a child risks going into shock, glucose and carnitine should be administered immediately and treatment for acidosis (increased blood acidity) commenced. This treatment is vital. If it is commenced immediately, it can save the child from permanent brain damage.

Until the child is at least six years old, a carefully monitored dietary regime is essential. All protein in food contains the amino acids tryptophan and lysine. As these amino acids are not broken down normally in glutaric aciduria type 1, the amount of protein in food should be reduced. People with the disease require carnitine supplements, as otherwise a deficiency will develop. Vitamin B2 (riboflavin) can stimulate enzyme production and is often prescribed. From approximately the age of six the strict dietary regime can be relaxed without damage to the child, but in situations where the child is at risk, it may be temporarily re-introduced. Problems with chewing and swallowing, combined with strict dietary requirements, can cause various deficiencies. Therefore, the diet should be drawn up in consultation with a dietician with a thorough knowledge of metabolic diseases in children.

Feeding and swallowing difficulties can be so serious that it becomes essential to make an opening in the abdominal wall, with a feeding tube directly into the stomach (percutaneous endoscopic gastrostomy - PEG) through which all essential nutrients can be given in the form of solutions. The child can still be given the opportunity to taste food and drink. It is important to take effective measures before the child starts to lose weight.

If other illnesses present, or if an operation is to take place, the child must receive adequate supplies of fluids and energy, often intravenously. A high temperature (hyperthermia) may be caused by impaired functionality of the body’s central fluid and temperature regulatory systems. Serious situations associated with a very high temperature may sometimes be misinterpreted as the result of infections, and should be treated with large quantities of fluids, administered intravenously. It is extremely important to adjust nutritional and fluid levels to the body’s temperature as this interplay has a significant effect on the child’s well-being.

Muscular contractions can be helped with medication, including baclofen and diazepam. In cases of severe muscular contractions a surgical procedure makes it possible to use a pump to release baclofen directly into the spinal fluid. Trihexyphenidyl can help alleviate dystonia. The botulinum toxin (Botox) is prescribed on the same basis as for other diseases.

Scoliosis (abnormal curvature of the spine) affects posture, and occasionally breathing. Such abnormalities require the help of an orthopaedic surgeon. Some children require treatment and following up by a physiotherapist, and in the case of severe abnormalities an operation may be necessary.

The child and his/her family require early contact with a habilitation team made up of professionals with special expertise in how disability affects everyday life, health and development. This team offers support and treatment within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes 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. Parents and siblings may also receive support.

The various habilitation measures are based on the needs and abilities of the individual child and are planned and carried out in collaboration with the child, parents and staff of pre-school and school.

To ensure the child develops communication skills it is important to stimulate speech development by means which include augmentative and alternative communication (AAC).

Regular contact with a physiotherapist is important in stimulating motor skills and preventing deformities.

The local authority can offer different forms of support to facilitate the family’s everyday life. Respite care including personal assistance, a contact family or short-term residential care, are examples of support measures.

Adults with the disease receive corresponding support and treatment within adult health care services and follow individual habilitation programmes. Resources for adults with the disease are unevenly distributed throughout Sweden. For this reason, preparations for the transfer of young people with the disease to adult health care services should start early.

Practical advice

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National and regional resources in Sweden

In Sweden, there are regional units with expertise in the areas of paediatric neurology and/or metabolic diseases.

There is a team specialising in metabolic diseases based at Karolinska University Hospital, Huddinge, Sweden. Tel: +46 8 585 80 000. (From 2012-04-01 the unit will move to Solna, Sweden. Tel: +46 8 517 70 000). The team offers a regional, round-the-clock service for doctors. Tel: +46 70 01671337.

A similar group is organised at the Queen Silvia Children’s Hospital, Sahlgrenska University Hospital in Gothenburg, Sweden. Tel: +46 31 343 41 00. (Contact Dr Niklas Darin or the secretary in charge.)

Urine analysis

Clinical chemistry laboratories which can analyse organic acids in urine samples are located at Sahlgrenska University Hospital/Sahlgrenska in Gothenburg and Karolinska University Hospital, Huddinge in Stockholm, Sweden.

Enzyme analysis

Central Laboratory for Clinical Chemistry, Sahlgrenska University Hospital/Sahlgrenska, Gothenburg, Sweden. Contact Associate Professor Elisabeth Holme.

CMMS, Karolinska University Hospital, Solna in Stockholm, Sweden. Contact Associate Professor Ulrika von Döbeln.

DNA analysis

Rigshospitalet in Copenhagen, Denmark carries out DNA-based diagnosis.

Resource personnel

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

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

Paediatrician Ricard Nergårdh, Astrid Lindgren Children’s Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 00 00, email: ricard.nergårdh@ki.se.

Associate Professor Anna Nordenström, Astrid Lindgren Children’s Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 00 000, email: anna.nordenstrom@ki.se.

Specialist Physician Annika Reims, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: annika.reims@vgregion.se.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

RBU, The Swedish National Association for Disabled Children and Young People, St Eriksgatan 44, Stockholm. Mailing address: Box 8026, SE-104 20 Stockholm, Sweden. Tel: +46 8 677 73 00, fax: +46 8 677 73 09, email: info@rbu.se, www.rbu.se.

The Organic Acidemia Association (OAA) is located in the US. www.oaanews.org, email: cswelch1@verizon.net.

Courses, exchanges of experience for personnel

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Research and development (R&D)

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Information material

An information leaflet on glutaric aciduria type 1 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 2011-11-24.) 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.

Information in Danish on glutaric acid type 1 may be obtained from Sjaeldne Handicap, Servicestyrelsen, Denmark. www.csh.dk. (Search for glutarsyreuri under Sjaeldne diagnose.)

Information in Norwegian on glutaric acid type 1 may be obtained from Frambu, Senter for sjeldne funktionshemningar, in Norway, www.frambu.no/glutarsyreuri-type-1.

Literature

Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF. Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis 1999; 22: 867-881.

Couce MA, Castiñeiras DE, Bóveda MA, Baña A, Cocho JA, Iglesias AJ et al. Evaluation and long-term follow-up of infants with inborn errors of metabolism identified in an expanded screening programme. Mol Genet Metab 2011; 104: 470-475.

Hartley LM, Khwaja OS, Verity CM. Glutaric aciduria type 1 a nonaccidental head injury. Pediatrics 2001; 107: 174-175. Kommentar i Pediatrics 2002; 109: 554.

Jafari P, Braissant O, Bonafé L, Ballhausen D. The unsolved puzzle of neuropathogenesis in glutaric aciduria type I. Mol Genet Metab 2011; 104: 425-437.

Kafil-Hussain NA, Monavari A, Bowell R, Thornton P, Naughton E, O’Keefe M. Ocular findings in glutaric aciduria type 1. J Pediatr Ophthalmol Strabismus 2000; 37: 289-293.

Kölker S, Garbade SF, Greenberg CR, Leonard JV, Saudubray JM, Ribes A et al. Natural history, outcome and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 2006; 59: 840-847.

Kölker S, Christensen E, Leonard JV, Greenberg CR, Burlina AB, Burlina AP et al. Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I). J Inherit Metab Dis 2007; 30: 5-22.

Kölker S, Christensen E, Leonard JV, Greenberg CR, Boneh A, Burlina AB et al. Diagnosis and management of glutaric aciduria type I—revised recommendations. J Inherit Metab Dis 2011; 34: 677-694.

Lutcherath V, Waaler PE, Jellum E, Wester K. Children with bitemporal arachnoid cysts may have glutaric aciduris type 1 (GA1); operation without knowing may be harmful. Acta Neurochir (Wien) 2001; 142: 1025-1030.

Zschocke J, Quak E, Guldberg P, Hoffmann GF. Mutation analysis in glutaric aciduria type 1. J Med Genet 2000; 37: 177-181.

Wiley V, Carpenter K, Wilcken B. Newborn screening with tandem mass spectrometry: 12 months’ experience in NSW Australia. Acta Paediatr (suppl) 1999; 88(432): 48-51.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: glutaric aciduria type 1

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 Mårten Kyllerman, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

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

Date of publication: 2012-06-19
Version: 1.1
Publication date of the Swedish version: 2011-12-30

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, fax +46 31 786 55 91, email: ovanligadiagnoser@gu.se.

 

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