Glycogen storage disease type 7 (GSD7), also called muscle phosphofructokinase deficiency or Tarui's disease, is a rare inherited disease, caused by homozygous or compound heterozygous mutation in the PFKM gene.
The most peculiar symptoms of Tarui disease are muscle weakness and muscle fatigue. Severity of these symptoms depends on individual’s enzyme activity levels. Recently the disease has been classified into four types .i.e. infantile form which is seen in neonates, classic form which manifests in childhood, late-onset form that presents in people at the age of 40-50 years and haemolytic form which is seen only in very few individuals. The onset generally occurs in childhood but sometimes people remain asymptomatic till adulthood.
Muscle fatigue generally resolves rapidly with rest, but after strenuous activities symptoms may remain for days. The disease can cause muscle pain, cramping and lower back pain, but the severity of symptoms in the muscles varies a lot amongst individuals with the disease.
During studies no consistent second wind phenomenon was found in Glycogen Storage Disease type 7 as it is seen in GSD type 5. The reason for absence of the second wind phenomenon being inability to properly metabolize blood glucose .
Symptoms begin when muscles do not receive sufficient energy to function regularly. As a result of this, there is muscle-cell energy crisis, due to which there is cell damage and degeneration. The condition causes pain, cramping, weakness and muscle stiffness in activities involving exertion, for example walking, running, carrying or lifting. In few cases muscle activity, demanding energy, results in breakdown of muscle protein resulting in increased production of uric acid. This uric acid may lead to painful inflammation of the joints (gout).
When muscle cells are damaged, myoglobin, the element that gives muscles their red colour, leaks from muscle cells into the blood plasma. Hence, when the blood plasma is filtered through the kidneys the urine appears red (myoglobinuria).
Myoglobinuria is a serious complication requiring urgent hospital care, as very high concentrations of myoglobin in blood plasma results in kidney damage. Few patients may need dialysis because of acute renal failure. A case of acute renal failure secondary to rhabdomyolysis has also been reported .
In a study where a patient was followed for several years various neurological symptoms attributable to Tarui’s disease were found like diplopia, complex partial seizure, hyporeflaxia, central facial palsy and weakness of upper extremity  .
There has been an association identified between PFK-M deficiency and increased leakage of calcium ions into the RBC. This abnormal high concentration of calcium ions decreases the elasticity of red blood cell membranes, which accelerates the rate of haemoysis and hence patient may also present with jaundice. The increased calcium ion content in the red blood cells sometimes disturbs the cell membranes, which may trigger the coagulation process. This may result in the development of blood clots and cardiovascular complications.
Physical examination findings may be normal and hence, thorough patient history and laboratory studies must be carried out to diagnose this condition.
A creatine kinase level in all cases of suspected glycogen storage disease is a must. In Tarui’s disease, the creatine kinase levels are elevated. Fasting glucose is indicated as hypoglycemia is found in glycogen storage diseases and it may lead to hypoglycemic seizures. Red blood cell examination indicates moderate haemolytic anaemia.
Urine studies are needed to find if myoglobinuria is present. In case of Tarui’s, disease myoglobinuria is seen after exercise.
Liver function tests are carried out as Hepatic failure may occur in patients with Tarui’s disease. Biochemical assay reveals normal phosphorylase activity. Phosphofructokinase is absent on histochemistry assay.
Ischemic forearm test can be performed to diagnose any muscle disorder. In case of Tarui’s disease this test is positive.
Glycogen and PFKM concentrations can be measured by microscopic analysis of biopsied muscle tissue, usually taken from the outer thigh.
DNA-based diagnostics can be used to identify the PFKM mutation.
There is currently no cure for Tarui’s disease, but various treatments can help to palliate symptoms and complications. Diet therapy is helpful in certain cases. Following the dietary advise religiously may reduce liver size, prevent hypoglycemia, and allows growth and development of patients suffering from it.
It is seen that a high-protein diet may provide increased muscle function in patients with weakness or exercise intolerance. Evidence also exists that a high-protein diet may slow or arrest progression of the disease. Drugs can be used to reduce uric acid concentration in the body as hyperuricemia leads to gout.
Avoidance of intense exercise helps in amelioration of symptoms. Genetic counseling of the patient along with the family must be done.
As there is no cure available for this condition, prognosis of the disease will depend on the individual. Most of the people suffering from this disease lead a normal life provided they avoid intense muscular activity. Once the cause of this condition is known, it becomes easier for the individual to get along with those around them, as they know now what can be expected from themselves.
The disease is caused due to mutation in a gene known as PFKM, which controls the production of the enzyme phosphofructokinase. In Tarui disease, the pattern of inheritance is autosomal recessive. This means that both the parents are healthy carriers of the mutated gene. Hence, during each pregnancy there is a 25% chance of the offspring inheriting double copies of the mutated gene and suffering from the disease. In a study, 5 patients with muscle phosphofructokinase deficiency, from different regions of Italy, were found to have 4 novel genetic mutations .
Tarui’s disease is a very rare condition and has been diagnosed only in few families in Sweden. It is estimated that only 10 people in Sweden are affected. In the international medical literature, approximately 100 cases have been reported till date.
It generally manifests right from childhood, but later onset correlates with a less severe form. The disease appears to be prevalent amongst people of Ashkenazi Jewish descent.
In cells, the PFKM enzyme is needed in the energy-yielding breakdown of glucose. The body receives its regular supply of glucose from the food directly or through the breakdown of reserved glycogen. Glycogen is a polysaccharide which stores energy mainly in liver and the muscles. PFK deficiency hampers the normal breakdown of glucose as it catalyses the rate-limiting step in glycolysis. The enzyme deficiency decreases the rate of conversion of fructose-6-phosphate to fructose-1,6-diposphate, thereby slowing down the breakdown of glycogen which results in accumulation of glycogen in muscles. PFK is a complex enzyme, comprising 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 merged depends on the tissue where the enzyme is situated.
In Tarui disease, there is a congenital deficiency of one of these subunits, i.e. the muscle (M) subunit of PFKM, due to which the muscles are affected. But, in red blood cells there is a mixture of equal parts of M and L subunits; hence there is only a partial absence of the enzyme in these cells, approximately 50 per cent.
Studies were conducted to investigate the effect of phosphofructokinase deficiency in tissues other then skeletal muscles by using mice for the experiments .
Studies revealed that the phosphofructokinase deficient mice suffered from severe hemolysis, compensatory reticulocytosis, splenomegaly and cardiac hypertrophy. In one study, a man suffering from phosphofructokinase deficiency presented with portal and mesenteric vein thrombosis .
There are no guidelines for the prevention of Glycogen storage disease type 7.
Glycogen Storage Disease Type 7 or Muscle phosphofructokinase (PFK) deficiency disease or Tarui’s Disease, is a rare form of glycogen storage disease characterized by exertional fatigue and muscular exercise intolerance. It is an autosomal recessive condition caused by mutations in PFKM gene. It occurs in childhood.
Tarui’s disease is a genetic disorder caused due to mutation of PFKM gene. It is an autosomal recessive condition meaning both parents should pass on the defective gene to their offspring so that the disease can manifest itself. Due to this genetic mutation there is defect in synthesis of glucose which is needed by the body to generate energy. Glucose is synthesized from glycogen and during this process phosphofructokinase is needed as a catalyst but due to its deficiency this process doesn’t take place and hence glucose is not available and glycogen deposits increase in the muscles.
Due to this unavailability of glucose for energy the individual presents with fatigue, tiredness, cramps and weakness on exertion. Sometimes in order to provide energy to the body, muscle proteins breakdown leading to production of uric acid. This uric acid forms crystals and affects the joints of the body leading to gout. When these muscles are damaged they release myoglobulin which is excreted through kidneys giving urine a brown color. This myoglobulin affects the kidneys and may lead to acute renal failure. This disease also affects the red blood cells of the body due to which they breakdown easily leading to jaundice and in severe cases may lead to liver failure.
Hence, the individual suffering from this disease should avoid intense muscular activity. They can carry out normal household work and jobs that do not involve much strenuous activity.
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. It is important that preschool and school staff are informed about the condition, with suggestions about suitable physical activities
Most people with the disease live normal lives as long as they avoid intensive muscle activity. 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 exertion.