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Tarui disease

This is part of Rare diseases.

Diagnosis: Tarui disease

Synonyms: Glycogenosis type VII, Phosphofructokinase deficiency

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Publication date: 2012-11-30
Version: 3.1

ICD 10 code

E74.0

The disease

Tarui disease, also known as phosphofructokinase deficiency, is caused by deficient activity of the enzyme phosphofructokinase (muscle PFK or PFKM) in muscle tissue. Glycogenosis type VII is another name for the disease. There are different forms of Tarui disease, whereof the classic type, with childhood onset, is the most common. Individuals with Tarui disease experience symptoms such as pain and muscle weakness, and sometimes muscle cramps or spasms, during intense physical activity (exercise intolerance).They may also experience mild jaundice caused by accelerated disintegration of red blood cells.

The disease was first described in 1965 by the Japanese physician Seiichiro Tarui and his co-workers. Tarui disease is one of twelve glycogen storage (glycogenosis) diseases. Two of the others are Pompe disease (glycogenosis type II) and McArdle disease (glycogenosis type V). Separate information on these diseases is available in the Rare Disease Database of the Swedish Board of Health and Welfare.

Occurrence

Tarui disease is a very rare condition and has only been diagnosed in a few families in Sweden. It is estimated that around 10 individuals in Sweden are affected. In the international medical literature, approximately 100 cases have been reported to date.

Cause

The disease is caused by a mutation in a gene known as PFKM, which governs the production of (codes for) the enzyme phosphofructokinase (muscle PFK or PFKM). The PFKM gene is located on the long arm of chromosome 12 (12q13.3). In cells, this enzyme is essential in the energy-yielding breakdown of glucose. The body obtains its supply of glucose directly from food or through the breakdown of stored glycogen. Glycogen is a polysaccharide that stores energy, primarily in the liver and muscles. PFK deficiency prevents the normal breakdown of glucose, which in turn slows the breakdown of glycogen, resulting in the accumulation of glycogen in muscles.

PFK is a complex enzyme, composed of three subunits, M, L, and P, coded by different genes. A functioning enzyme is made up of a combination of four of these three types of subunits. How these four are combined depends on the tissue where the enzyme is located. In Tarui disease there is a congenital deficiency of one of these subunits, muscle (M) subunit PFKM, which means that muscles are affected. However, in red blood cells there is a mixture of equal parts of M and L subunits, which means that there is only a partial absence of the enzyme in these cells, approximately 50 per cent. Glycogen is also found in the liver but because the M subunit is not a constituent of liver PFK (PFKL), the liver is not affected by Tarui disease.

Swedish researchers have identified an association between PFK-M deficiency and increased leakage of calcium ions into red blood cells. The abnormally high concentration of calcium ions reduces the elasticity of the red blood cell membranes, which is probably the direct cause of the accelerated disintegration of red blood cells (haemolysis) and jaundice in patients with Tarui disease.

Heredity

In Tarui disease the pattern of inheritance is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. In each pregnancy there is a 25 per cent risk that the child will inherit double copies of the mutated gene (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

Characteristic symptoms of Tarui disease include muscle weakness and muscle fatigue (exercise intolerance). Although the onset usually occurs in childhood, some people remain asymptomatic into adulthood. In recent years the disease has been classified into four types: infantile form, classic form, late-onset form, and the haemolytic form. The severe, infantile form of the disease presents in neonates. The classic form manifests in childhood, and the late-onset form typically presents in individuals in their 40s or 50s. The haemolytic form, associated with accelerated destruction of red blood cells, has only been reported in very few individuals.

Muscle fatigue usually resolves quickly with rest, but after strenuous activities symptoms may linger for days. The disease can cause muscle pain, cramping and lower back pain, but the severity of symptoms in the muscles varies widely among individuals with the disease.

Symptoms arise when muscles are not supplied with sufficient energy to function normally. This results in a muscle-cell energy crisis, resulting in cell damage and degeneration. The condition causes pain, cramping, weakness and muscle stiffness in activities involving exertion, such as walking, running, carrying or lifting. In some individuals muscle activity, demanding energy, leads to the breakdown of muscle protein. Imbalance in energy economy leads to increased production of uric acid, which may cause painful inflammation of the joints (gout).

When muscle cells are damaged, myoglobin, a substance which gives muscles their red colour, leaks from muscle cells into the blood plasma. This means that when the blood plasma is filtered through the kidneys the urine is coloured red (myoglobinuria). Myoglobinuria is a serious complication requiring acute hospital care, as very high concentrations of myoglobin in blood plasma results in kidney damage. Some myoglobinuria patients develop acute renal failure requiring dialysis.

An increased rate of haemolysis can lead to varying degrees of jaundice (icterus). In most cases the condition manifests as a yellow discolouration of the whites of the eyes. The increased calcium ion content in the red blood cells sometimes perturbs the cell membranes, which may trigger the coagulation process. This may result in the development of blood clots and cardiovascular complications.

In the infantile form of Tarui disease, symptoms present in neonates.The condition leads to early death, often as a result of infection or breathing problems.

Diagnosis

An investigation should be carried out to exclude other possible causes of jaundice. The diagnosis is then established by analysing PFK activity in the red blood cells. Usually, the test results show slightly lowered activity.

Glycogen and PFKM concentrations are measured in a microscopic analysis of biopsied muscle tissue, usually taken from the outer thigh.

DNA-based diagnostics can be used to identify the PFKM mutation.

At the time of diagnosis the family should be offered genetic counselling. Carrier and prenatal diagnostics, as well as pre-implantation genetic diagnostics (PGD) in association with IVF (in vitro fertilization), are available in families where the mutation is known.

Treatment/interventions

There is currently no cure for Tarui disease, but various treatments may alleviate symptoms and complications.

Individuals with Tarui disease should be observant to myoglobulinuria, presenting as a dark discoloration of the urine. Owing to the risk of kidney damage, medical help should be sought immediately if symptoms arise. Dialysis is sometimes needed if toxic waste products have accumulated in blood plasma (uraemia).

In Tarui disease, jaundice is generally mild and does not require treatment.

Individuals affected by recurrent blood clotting should undergo a blood coagulation investigation and may require anticoagulant medication.

High uric acid concentrations that may cause gout can be treated with drugs that lower uric acid levels in the blood.

The effectiveness of dietary management remains unclear. It is possible that food with a high fat content, notably fatty fish, has a beneficial effect, as the glycerol (glycerine) in neutral fat can replace glucose as a better source of energy. It may be possible to accustom the skeletal muscle cells to oxidise fatty acids rather than glucose to produce energy.

Individuals with Tarui disease should avoid intensive muscle activity. Avoiding all physically demanding work in order to alleviate symptoms is not recommended as physical inactivity has many negative consequences for physical and mental health. Individual advice and help with designing a suitable exercise programme can be provided by a physiotherapist.

Individuals with Tarui disease can usually carry out household work and jobs not requiring strenuous muscle effort, although all activities must be adapted to the limitations imposed by reduced muscle functionality. Depending on the individual’s degree of functional disability, new work routines, and individualized adaptations and aids may be necessary to help in daily life. If required, the school, home, car and workplace can be adapted to individual needs. An occupational therapist can be contacted for assistance.

It is important that preschool and school staff are informed about the condition, with suggestions about suitable physical activities. These should be adapted to suit the individual needs of the child. Some families may need the help of a habilitation team including professionals with special expertise in how disability affects everyday life, health and development. Support and treatment are offered within the medical, educational, psychological, social and technical fields. The measures focus on existing needs, may vary over time and are implemented in collaboration with individuals close to the child.

Most people with the disease live normal lives as long as they avoid intensive muscle activity, and the need for treatment is highly individual. Once the causes of the condition have been explained, it may be easier for individuals to deal with their own expectations and those of people around them. It may also be easier to make choices about education and training as well as suitable sports. It is important to avoid occupations requiring a great deal of physical exertion.

Practical advice

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National and regional resources in Sweden

Enzyme analyses of red blood cells (analyses of PFK and other enzymes) are carried out at the Department of Clinical Chemistry, Sahlgrenska University Hospital/Sahlgrenska, SE-413 45 Göteborg, Sweden. Tel: +46 31 342 41 00 (Professor Elisabeth Holme).

Resource personnel

Professor Gunnar Ronquist, Department of Clinical Chemistry, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 42 44, fax: +46 18 611 37 03, email: gunnar.ronquist@akademiska.se.

Chief physician Anna-Lena Nilsson, Paediatric Clinic, Östersund Hospital, SE-831 83 Östersund, Sweden. Tel: +46 63 15 39 77, email: anna-lena.nilsson@jll.se.

Courses, exchanges of experience, recreation

In the autumn of 2013 a large international conference on glycogen storage diseases was held in Heidelberg, for professionals as well as patients. Information available at: www.worldgsd.org

Organizations for the disabled/patient associations etc.

The Scandinavian Association for Glycogen Storage Disease, SAGSD, was founded in Sweden and is a Scandinavian network for people with glycogen storage diseases and their relatives. Contact Marcus Landgren, postmaster@sagsd.org, www.sagsd.org.

There is an American Association for Glycogen Storage Diseases, P.O. Box 896, Durant, IA 52747, email: maryc@agsdus.org, www.agsdus.org.

RBU, The Swedish National Association for Disabled Children and Young People, St Eriksgatan 44, 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.

NHR, The Swedish Association for Persons with Neurological Disabilities, St Eriksgatan 44, Box 49084, SE-100 28 Stockholm, Sweden. Tel: +46 8 677 70 10, fax: +46 8 677 13 15, email: nhr@nhr.se, www.nhr.se.

Courses, exchanges of experience for personnel

In the autumn of 2013 a large international conference on glycogen storage diseases was held in Heidelberg, for professionals as well as patients. Information available at: www.worldgsd.org.  

Research and development

Research is currently ongoing to establish the genetic association between PFK deficiency and the defect in red blood cell membranes which causes increased calcium ion leakage in the cell. The project is headed by Professor Gunnar Ronquist, Department of Clinical Chemistry, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 42 44, fax: +46 18 611 37 03, email: gunnar.ronquist@akademiska.se.

Information material

An information leaflet on Tarui disease summarising 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 2012-4-12). 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 American Association for Glycogen Storage Diseases has a website with information on these diseases: www.agsdus.org.

Literature

Toscano A, Musumeci O. Tarui disease and distal glycogenoses: clinical and genetic update. Acta Myol 2007; 26: 105-107.

Finsterer J, Stöllberger C. Progressive mitral valve thickening and progressive muscle cramps as manifestations of glycogenosis VII (Tarui’s disease). Cardiology 2008; 110: 238-240.

Finsterer J, Stöllberger C, Kopsa W. Neurologic and cardiac progression of glycogenosis type VII over an eight-year period. South Med J 2002; 95: 1436-1440.

Makajima H, Raben N, Hamaguchi T, Yamasaki T. Phosphofructokinase deficiency; past, present and future. Curr Mol Med 2002; 2: 197-212.

Musumeci O, Bruno C, Mongini T, Rodolico C, Aguennouz M, Barca E et al. Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII). Neuromuscul Disord 2012; 22: 325-330.

Ozen H. Glycogen storage diseases: new perspectives. World J Gastroenterol 2007; 13: 2541-2553.

Ronquist G, Rudolphi O, Engström I, Waldenström A. Familial phosphofructokinase deficiency is associated with a disturbed calcium homeostasis in erythrocytes. J Intern Med 2001; 249: 85-95.

Ronquist G. Glycogenosis type VII (Tarui’s disease); diagnostic considerations and late sequalae. South Med J 2002; 95: 1361-1362.

Rudolphi O, Ek B, Ronquist G. Inherited phosphofructokinase deficiency associated with hemolysis and exertional myopathy. Eur J Haematol 1995; 55: 279-281.

Rudolphi O, Brattsand G, Waldenström A, Nilsson AL, Ronquist G. Ovanlig typ av hemolys vid Taruis sjukdom i två familjer av västerbottniskt ursprung. Läkartidningen 2006; 103: 657-660.

Tarui S, Okuno G, Ikura Y, Tanaka T, Suda M, Nishikawa M. Phosphofructokinasedeficiency in skeletalmuscle. A new type of glycogenosis. Biochem Biophys Res Commun 1965; 19: 517-523.

Toscano A, Musumeci O. Tarui disease and distal glycogenoses: clinical and genetic update. Acta Myol 2007; 26: 105-107.

Waldenström A, Engström I, Ronquist G. Increased erythrocyte content of calcium ions in patients with Tarui’s disease. J Intern Med 2001; 249: 97-102.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim
Search: glycogen storage disease VII

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 Professor Gunnar Ronquist, Uppsala University Hospital, 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.

Publication date: 2012-11-30
Version: 3.1
Publication date of the Swedish version: 2012-09-10

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, 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.