Date of publication: 2011-06-21
Version: 2.0
E70.2
Tyrosinemia type 1 belongs to a group of rare, inherited metabolic disorders caused by impaired breakdown of tyrosine. Tyrosine is one of the 20 amino acids found in all proteins. When the body has used all the tyrosine it needs for protein production, the excess is normally degraded. If this metabolic process is defective, as in tyrosinemia type 1, toxic products accumulate, thereby causing liver and kidney damage.
There are several different types of Tyrosinemia. This text deals primarily with type 1, which is the most prevalent and most severe form. There is both an acute and a chronic form of tyrosinemia type 1. The acute variant is more prevalent.
The disorder was first described in 1956 by Margaret D. Baber. In 1965, Swedish physician Rolf Zetterström and collaborators published an extensive description of the disorder, and in 1977 Bengt Lindblad and collaborators described the enzyme defect that underlies the condition.
The estimated global incidence of tyrosinemia in newborns is 1 per 100,000, but the geographical variation is wide and the number is probably lower in most countries. The condition is more prevalent in Scandinavia and in one region of Canada than in other parts of the world. In Sweden, approximately one baby per year is diagnosed.
Tyrosimemia type 1 is caused by mutations in a gene governing the production of the enzyme fumarylacetoacetase (FAH). The FAH gene is located on the long arm of chromosome 15 (15q23-q25). The body needs FAH to break down tyrosine, and individuals with tyrosinemia have little or no FAH. When the breakdown of tyrosine is inhibited, toxic metabolic products accumulate, causing liver and kidney damage.
These metabolic products are also converted into succinylacetone, which inhibits another enzyme in a different metabolic pathway. In the chronic form of tyrosinemia type 1, this enzyme deficiency causes the same symptoms as in acute intermittent porphyria, including abdominal pain, high blood pressure and neurological symptoms. Separate information on acute intermittent porphyria is available in the rare disease database of the Swedish National Board of Health and Welfare.
The inheritance pattern of tyrosinemia 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.
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.
Children with tyrosinemia type 1 may present with a number of different symptoms, including failure to thrive, fever, vomiting, diarrhoea, enlarged liver or liver failure, excessive abdominal fluids (ascites), jaundice, impaired kidney function, rickets, and liver tumours.
The onset of the acute form occurs during the first few months of the child’s life. Symptoms include failure to thrive, fever, diarrhoea, bloody stools and vomiting. The liver is enlarged and jaundice may present. Increased tendency to bleed, particularly nose bleeds, is common. Other symptoms include enlarged spleen, and swollen abdomen and legs. Seriously ill children may have a particular smell, reminiscent of cabbage. Without treatment the condition is life-threatening owing to liver failure and coagulation disturbances.
The onset of the chronic form is gradual and the symptoms less severe. Some children develop symptoms around the age of 1 year, while in others the condition may not be noticeable until school age. The abdomen is distended owing to liver and spleen enlargement, and bone abnormalities are caused by rickets. The primary cause of rickets is impaired renal function, of a type that resembles a kidney defect called Fanconi syndrome. Impaired liver function, with ensuing complications, is common. Accumulation of succinylacetone gives rise to the same symptoms as in acute intermittent porphyria, a disorder caused by impaired production of the red blood pigment heme: abdominal pain, polyneuropathy (peripheral nerve damage) and high blood pressure. An ultrasound examination will reveal a thickened heart muscle. Without treatment, these children develop liver failure and malignant liver tumours, which may be fatal.
High blood concentrations of tyrosine may also cloud the corneas, thereby impairing vision.
In most cases the diagnosis is made when the child presents with symptoms that call for further investigation. Examinations include analyses of organic acids, amino acids, and alpha-fetoprotein.
Various attempts have been made to detect babies with tyrosinemia in association with PKU screening. At present, however, no such test is performed as current screening methods are still unreliable.
If the specific mutation in a family is known, DNA analysis can be used to establish the diagnosis. If the familial mutation is known it is also possible to carry out prenatal diagnostics. In most cases this can be performed during the embryonic period of pregnancy, or it can be carried out in the foetal period. Prenatal diagnosis can also be carried out by measuring the concentration of succinylacetone in amniotic fluid and the level of FAH enzyme in amniotic fluid cells.
Tyrosinemia type 1 is treated with dietary therapy, medical treatment, and liver transplantation. Children with tyrosinemia type 1 should be cared for by a medical centre specialising in inherited metabolic disorders, where specialised physicians and dieticians collaborate with geneticists, chemists, psychologists and counsellors. These centres also keep updated with research and development related to the disease. The centre should be responsible for making a treatment and follow-up plan, which is continuously updated and used as a guide for treatment.
Regular monitoring of the condition can in part be carried out by the healthcare services in the home community. The number of visits is adjusted for age and symptoms. Regular examinations should also be performed at a metabolic centre, where physicians and dieticians evaluate test results, keep the patient updated about the latest developments in dietary therapy and other treatments, and plan future treatment in consultation with the person who has the disorder and his or her family.
Previously, dietary restrictions and liver transplantation were the only treatment options for tyrosinemia. Dietary treatment normalized liver and renal functions, but in the long run could not prevent shortened life expectancy. Nitisone, discovered by Swedish physicians, has revolutionized tyrosinemia treatment. This drug prevents the accumulation of toxic metabolic products, and individuals with tyrosinemia can expect to become symptom-free.
Nitisone treatment was introduced in 1991. Since then, life expectancy has increased dramatically. When dietary therapy was the only treatment option, only 29 per cent of those diagnosed with tyrosinemia before the age of 2 months survived beyond a two year period. The corresponding number for those who received nitisone in combination with dietary restrictions is over 90 per cent. The combination of medical treatment and diet has also enabled these children to grow normally, and has improved liver function. When the kidneys recover, rickets also heal.
Dietary restrictions are still an essential part of treatment. Food energy content should be monitored and the intake of the amino acids phenylalanine and tyrosine should be strictly regulated. The diet should be adjusted to individual needs and the protein content must remain high enough for the child to grow normally. Protein substitutes specially designed for children and adults with tyrosinemia type 1 are available.
With the help of blood tests it is possible to monitor the intake of phenylalanine and tyrosine, so that the levels are neither too high, nor too low. Treatment is lifelong and requires considerable commitment.
If the liver is severely damaged, there is a risk of acute liver failure, which is a life-threatening condition. Should this complication arise, liver transplantation must be considered. A transplant should also be considered in those few cases where nitisone treatment does not have the intended effect. Transplantation results have been good, but this is a risky treatment that requires lifelong immunosuppressant therapy.
Vitamin D supplements may be considered for treatment of rickets.
Some of these children may require habilitation. A habilitation team includes professionals with special expertise in disabilities and their impact on health, development and everyday life. Support and treatment take place within the medical, educational, psychological, social and technical fields. Help includes assessment, treatment, the provision of aids, information on the specific disability, and counselling. It may also include 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 can also receive support. The measures focus on existing needs, may vary over time and occur in collaboration with individuals close to the child.
Dietary therapy requires commitment to precision, patience, and inventiveness, and despite the restrictions it is important that children with tyrosinemia find mealtimes pleasurable. The whole family must be aware of the rules pertaining to diet, and the food served should, as far as possible, be similar for all. It is a good idea to have contact with other parents in the same situation, for exchange of tips and advice on how to make the children enjoy their meals. Sometimes this may be achieved by serving dishes that children particularly like, often with a higher fat or sugar content.
The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.
The Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.
Associate Professor Ulrika von Döbeln, Center for Inherited Metabolic Diseases, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00, email: ulrika.vondobeln@karolinska.se.
Dietician Karina Eftring, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: karina.eftring@vgregion.se.
Professor Elisabeth Holme, Clinical Chemistry, Sahlgrenska University Hospital/ Sahlgrenska, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00, email: elisabeth.holme@clinchem.gu.se.
Associate Professor Bengt Lindblad, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: bengt.lindblad@vgregion.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.
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RFL, The National Association for liver disease, Box 2918, 187 29 Täby, Sweden. Email: kansli@rfl-lever.se, www.rfl-lever.se.
The Queen Silvia Children’s Hospital, in collaboration with the University of Gothenburg, arranges annual courses on inherited metabolic diseases, targeted to health professionals.
It has been established that the earlier nitisone treatment can be initiated, the lesser the risk of developing primary liver cancer. Therefore, a high priority is the development of a safe and efficient screening method. Early diagnosis would enable effective treatment before severe liver or kidney disease present, hopefully also preventing cancer.
Current knowledge on the underlying causes of the disease gives no indication that modern gene therapy is likely to replace the combination of nitisone and dietary therapy in the future.
An information leaflet on Tyrosinemia 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 2010-5-19) 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.
Baber MD. A case of congenital cirrhosis of the liver with renal tubular defects akin to those in the Fanconi syndrome. Arch Dis Child 1956; 31: 335-339.
Gentz J, Jagenburg R, Zetterstroem R. Tyrosinemia: An inborn error of tyrosine metabolism with cirrhosis of the liver and multiple renal tubular defects (de Toni-Debre-Fanconi syndrome). J Pediatr 1965; 66: 670-696.
Holme E, Lindstedt S. Nontransplant treatment of tyrosinemia. Clin Liver Dis 2000; 4: 805-814.
Koelink CJ, van Hasselt P, van der Ploeg A, van den Heuvel-Eibrink MM, Wijburg FA, Biljeveld CM et al. Tyrosinemia type 1 treated by NTBC: how does AFP predict liver cancer? Mol Genet Metab 2006; 89: 310-315.
Kvittingen EA, Guibaud PP, Divry P, Mandon G, Rolland MO, Domenichini Y et al. Prenatal diagnosis of hereditary tyrosinaemia type I by determination of fumarylacetoacetase in chorionic villus material. (Letter) Europ J Pediat 1986; 144: 597-598.
Lindblad B, Lindstedt S, Steen G. On the enzymic defects in hereditary tyrosinemia. Proc Nat Acad Sci 1977; 74: 4641-4645.
Lindblad B, Fällström SP, Hoyer S, Nordborg C, Solymar L, Velander H. Cardiomyopathy in fumarylacetoacetase deficiency (hereditary tyrosinaemia): a new feature of the disease. J Inherit Metab Dis 1987; 10; 319-322.
Masurel-Paulet A, Poggi-Bach J, Rolland MO, Bernard O, Guffon N, Dobbelaere D et al. NTBC treatment in tyrosinaemia type I: long-term outcome in French patients. J Inherit Metab Dis 2008; 31: 81-87.
Mitchell G, Grompe M, Lambert M, Tanguay R. Hypertyrosinemia. In The metabolic and molecular bases of inherited disease. Scriver et al eds. 8th ed. New York: McGraw-Hill; 2001; 1777-1805.
Santra S, Preece MA, Hulton SA, McKiernan PJ. Renal tubular function in children with tyrosinemia type 1 treated with nitisinone. J Inherit Metab Dis 2008; 31: 399-402.
Santra S, Baumann U. Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1. Expert Opin Pharmacother 2008; 9: 1229-1236.
OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim
Search: tyrosinemia
GeneReviews (University of Washington),
www.genetests.org (select GeneReviews, then Titles)
Search: tyrosinemia
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 Bengt Lindblad, 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: 2011-06-21
Version: 2.0
Publication date of the Swedish version: 2009-09-14
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.