Glycogenosis type VII (Tarui's disease): diagnostic considerations and late sequelae. (Editorial).

Elsewhere in this issue, Finsterer et al report a case of Tarui's disease and describe its neurologic and cardiac progression over a course of 8 years. Tarui's disease is a rare inborn error of metabolism involving a deficiency of the muscle isozyme of phosphofructokinase (PFK). Human PFK is a tetramer of peptide subunits; three types of subunit exist in the tissues, viz muscle type (PFK-M or A), liver type (PFK-L or B), and platelet (or brain) type (PFK-P or C), which are under separate genetic control. Human muscle and liver PFK consist of homotetramers (M4 and L4), whereas the human erythrocyte PFK is a heterotetramer containing the five isozymes, M4, M3L, M2L2, ML3, and L4. (1) Inherited deficiency of PFK-M in humans is associated with myopathy and/or hemolysis or an asymptomatic state. (2) The most common type, glycogenosis VII or Tarui's disease in its classical form, is characterized by the coexistence of muscle disease and moderate hemolysis. (3) The disease is inherited as an autosomal recessive trai t. In the Western hemisphere, PFK deficiency appears to be prevalent among people of Ashkenazi Jewish descent, and they share two common pathogenic mutations, a splicing defect and a nucleotide deletion, which account for approximately 95% of mutant alleles. (4) Phosphofructokinase is an allosterically regulated enzyme of the glycolytic pathway. Decreased enzyme activity in the red blood cells reduces the glycolytic flow, with a moderate decrease of ATP (15% to 20%) and a more pronounced decrease of 2,3-bisphosphoglycerate (BPG) (about 50%). (5) Decreased BPG concentration in the red blood cells reduces the oxygen delivery to the tissues, consequently stimulating erythropoietin release, which is thought to explain the lack of anemia despite often a mild indirect hyperbilirubinemia, which in turn is the result of ongoing hemolysis. (2) The myopathy manifests itself clinically by variable muscle weakness, occasional pain, seizures and muscle cramps, exercise intolerance, lumbar pain, and myoglobinemia and myogl obinuria due to more or less pronounced rhabdomyolysis. (6)

The case reported here deals with a 66-year-old woman with Tarui's disease diagnosed as late as age 62. In early childhood, the patient had had febrile convulsions, which resolved without therapy. The more organized symptoms of neurologic and subsequent cardiovascular origin started at the age of 40 to 50 years, having a progressive course. Beginning at age 48, she had elevated serum values of creatine kinase and lactate dehydrogenase, sometimes accompanied by muscle cramps but with no specific signs of myocardial infarction. Diagnosis was established in connection with muscle biopsy revealing increased glycogen storage and absent histochemical stain for PFK. Since age 66, she has had progressive exercise intolerance without a second wind phenomenon.

Pathomechanisms for myopathy are the impaired muscle PFK activity and the intracellular glycogen storage, leading to displacement and compression of the contractile system. (7) The authors mention in their report that increased fat oxidation after some time is responsible for the "second wind phenomenon, characterized by improved exercise capacity after an initial period of fatigue. Thus, dihydroxyacetonephosphate may be formed from the glycerol portion of triacylglycerols in the muscle catalyzed by glycerol kinase and glycerol-3-phosphate dehydrogenase. This means a metabolic bypass regarding glycolysis, since the triosephosphate, dihydroxyacetonephosphate, is a glycolytic intermediate after the PFK step. The authors also discuss storage of glycogen in central and peripheral axons, as well as in myocardium. This is compatible with the existence of muscle type isozymes in brain and heart, (8) in addition to the high amount of platelet-type PFK expression in these two tissues." (9)

A co-phenomenon to Tarui's disease (glycogenosis type VII) is the recent finding of an increased erythrocytic [Ca.sup.2+] content. (5,10) Because intraerythrocytic [Ca.sup.2+] can induce cell dehydration, phosphatidylserine flip-flop, and changes in membrane skeletal structure, it is conceivable that the patient's erythrocytes participated in those manifestations of the disease that involved a disturbed clot formation. Accordingly, such altered erythrocytes might well have been involved in the emerging symptoms of pulmonary embolism and myocardial infarction that were observed in the patient and that led to anticoagulation therapy for a long period. Hence, Tarui's disease shows many facets, and this may be why the diagnosis of this congenital disorder was not established until the patient was 62 years old.

Gunnar Ronquist, MD, PhD

Department of Medical Sciences

Clinical Chemistry

University Hospital

SE-751 85 Uppsala, Sweden

References

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(4.) Raben N, Sherman JB, Adams E, et al: Various classes of mutations in patients with phosphofructokinase deficiency (Tarui's disease). Muscle Nerve 1995 3:S35-838

(5.) Ronquist G, Rudolphi G, Engstrom I, et al: Familial phosphofructokinase deficiency is associated with a disturbed calcium homeostasis in erythrocytes. J Intern Med 2001; 249:85-95

(6.) Rowland LP, DiMauro S: Glycogen storage diseases of muscle: genetic problems. Res Publ Assoc Res Nerv Ment Dis 1983; 60:239-254

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(10.) Waldenstrom A, Engstrom I, Ronquist G: Increased erythrocyte content of [Ca.sup.2+] in patients with Tarui's disease. J Intern Med 2001; 249:97-102