Tarui's disease

ALSO KNOWN AS: Glycogenosis type VII; muscle phosphofructokinase deficiency

DEFINITION Tarui’s disease is both a glycogen storage disease and a glycolytic disorder. In glycogen storage diseases, ATP production in muscle tissue is impaired and excessive glycogen amounts are stored in muscles and other tissues. Glycolytic disorders feature a defect in one or more steps in glycogen metabolism. Tarui’s disease is caused by an inherited defect in the gene coding for phosphofructokinase (PFK), an enzyme that catalyzes the rate-limiting step in glycolysis.

Risk Factors

The main risk factor for Tarui’s disease is having a family member who has the disorder. The disease is especially prevalent among Ashkenazi Jewish individuals, with disease onset usually occurring in childhood.

Etiology and Genetics

Tarui’s disease is a glycogen storage disease in which the conversion of glycogen to glucose is impaired, resulting in the accumulation of glycogen in tissues. The defective glycogen is caused by a deficiency in PFK, which catalyzes the rate-limiting conversion of fructose-6-phosphate and fructose-1-phosphate to fructose-1,6-diphosphate. PFK occurs in three forms in humans, the muscle (PFK-M), liver (PFK-L), and platelet (PFK-P) isozymes. PFK-M is the most common form in skeletal muscle, heart, and brain and the only PFK isozyme that metabolizes glucose in muscle. Red blood cells, however, use both PFK-M and PFK-L.

Tarui’s disease is inherited as an autosomal recessive trait, meaning that an affected individual will receive one copy of the mutated gene from each parent. J. B. Sherman and colleagues found that the mutation occurs in two major forms in Ashkenazi Tarui’s disease patients, as a splicing mutation and as a deletion mutation. The splicing mutation, delta5, is a G to A point mutation at the 5′-splice donor site of 5 of the PFK muscle subunit (PFKM) gene, resulting in the complete deletion of exon 5 from the PFKM mRNA transcript. The delta5 mutation was detected in eleven out of eighteen (60 percent) mutated genes in nine Ashkenazi families affected by the disease. The deletion mutation, which involves deletion of a single base in exon 22, was observed in six out of seven (86 percent) mutated genes in the nine Ashkenazi families. Together, these two mutations accounted for 94 percent of the total mutated genes detected in the members of these families. In contrast, the delta5 gene was detected in only one out of 250 normal Ashkenazi individuals. Mutations in other exons and in an intron between exon 10 and exon 11 have also been associated with the Tarui’s disease phenotype.

These pathogenic PFKM mutations cause the muscle symptoms of Tarui’s disease, including muscle weakness and exercise intolerance. Because PFK-M is used by red blood cells to metabolize glucose, these mutations can also cause red blood cell impairment in the form of reticulocytosis and hemolysis. Currently, patients with symptoms of Tarui’s disease may be genetically tested by a sequencing assay on DNA extracted from muscle tissue. Healthcare practitioners will usually offer patients the option of genetic counseling if they are considering genetic testing, especially because there is no specific treatment for Tarui’s disease.

Symptoms

Tarui’s disease symptoms include muscle weakness, cramps, and exercise intolerance, referring to the excessive fatigue experienced in response to exercise. Some patients experience hemolysis with jaundice or severe renal impairment. This results in muscle necrosis and myoglobinuria, in which myoglobin is released from muscle cells and excreted in the urine, which appears rust-colored. In some cases, myoglobin accumulates in the kidney tubules, causing severe renal insufficiency. The phosphofructokinase defect also affects red blood cells, thus some patients have hemolysis with hyperbilirubinemia or jaundice.

Screening and Diagnosis

Physical examination often does not reveal abnormalities. Taking a patient’s history, including response to exercise and family medical history, and lab testing are the most useful tools for diagnosing this disease. If risk factors are identified, laboratory testing is performed. Frequently, a creatine assay is performed on a blood specimen and a myoglobinuria assay is conducted on a urine specimen. Elevated creatine kinase and positive myoglobinuria, especially after exercise, are warning signs of Tarui’s disease. Another common assay determines the presence of the PFK by immunohistochemistry, which involves the binding of PFK-specific antibodies to PFK, if present in the specimen. The absence of PFK implies Tarui’s disease. The ischemic forearm test is also frequently performed as a Tarui’s disease screening test. In this assay, the patient grasps an object once or twice per second for two to three minutes while a blood pressure cuff is inflated on his or her upper arm. After the patient relaxes his or her grip, creatinine kinase, ammonia, and lactate levels are assayed at five-, ten-, and twenty-minute intervals. A positive ischemic forearm test, suggesting Tarui’s disease, is the lack of lactate elevation as ammonia levels rise. Healthy subjects are expected to demonstrate increases in both lactate and ammonia levels. If one or more of these laboratory tests are positive, a muscle biopsy is required for a definitive diagnosis. When the muscle sample is examined under a microscope, the presence of subcarcolemmal vacuoles, abnormal polysaccharide deposits in muscle fibers, or abnormal red blood cells are positive findings for Tarui’s disease.

Treatment and Therapy

Currently, there is no curefor Tarui’s disease, although diet modifications and rest have been shown to be effective for decreasing clinical symptoms. Oral intake of glucose or fructose may also improve exercise tolerance. Most treatment programs for Tarui's disease involve instructing patients to avoid strenuous exercise and avoid foods high in carbohydrates.

Prevention and Outcomes

Tarui’s disease symptoms can be avoided by minimizing strenuous exercise and by observing a low-carbohydrate, high-protein diet, especially for less severe cases where disease onset occurs later in childhood or in adulthood.

Bibliography

Cheng, Liang, et al. Molecular Genetic Pathology. 2d ed. New York: Springer, 2013. Print.

Fletcher, H. L., and G. I. Hickey. Genetics. New York: Garland Science, 2013. Print.

"Glycogen Storage Disease Type 7." National Organization for Rare Disorders, 12 Nov. 2020, rarediseases.org/rare-diseases/glycogen-storage-disease-type-vii/. Accessed 9 Sept. 2024.

Gray, R. G. F., et al. “Inborn Errors of Metabolism as a Cause of Neurological Disease in Adults: An Approach to Investigation.” Journal of Neurology, Neurosurgery & Psychiatry 69 (2000): 5–12. Print.

Raben, N., et al. “Various Classes of Mutations in Patients with Phosphofructokinase Deficiency (Tarui’s Disease).” Muscle & Nerve 3 (1995): S35–S38. Print.

Sherman, J. B., et al. “Common Mutations in the Phosphofructokinase-M Gene in Ashkenazi Jewish Patients with Glycogenesis vII—and Their Population Frequency.” The American Journal of Human Genetics 55 (1994): 305–13. Print.

Vasconcelos, O., et al. “Nonsense Mutation in the Phosphofructokinase Muscle Subunit Gene Associated with Retention of Intron 10 in One of the Isolated Transcripts in Ashkenazi Jewish Patients with Tarui Disease.” The Proceedings of the National Academy of Sciences 92 (1995): 10322–326.

Wiggins, Jennifer, and Anna Middleton. Getting the Message Across: Communication with Diverse Populations in Clinical Genetics. Oxford: Oxford UP, 2013. Print.