Neurologic and cardiac progression of glycogenosis type VII over an eight-year period. (Case Reports).

ABSTRACT: Little is known about the progression of phosphofructokinase deficiency (glycogenosis type VII, Tarui's disease). We describe a 66-year-old woman who had this disease diagnosed in 1997. Initial manifestations had included simple partial seizures since 1977, anginal chest pain since 1982, and muscle cramps since 1983. To prevent recurrent myocardial infarction, anticoagulation therapy with phenprocumon was initiated. Cardiac involvement progressed over an 8-year period, manifesting as low-voltage electrocardiogram (ECG), ectopic supraventricular tachycardia, thickened mitral valve, mitral valve insufficiency, enlarged left atrium, left ventricular hypertrophy, and diastolic dysfunction. Progression of neurologic involvement manifested as complex partial seizures, double vision, reduced tendon reflexes, central facial palsy, bradydiadochokinesia, and distal weakness of the upper extremities. Discontinuance of oral anticoagulation after 19 years, initiation of enalapril therapy, and administration of c arbamazepine markedly improved the patient's condition.

**********

ALTHOUGH about 40 families with autosomal recessive muscle phosphofructokinase deficiency (glycogenosis type VII, Tarui's disease) have been reported, (1) little is known about the long-term course and progression of the disease. (2,3) We describe a patient with progressive cardiac and neurologic manifestations of the disease.

CASE REPORT

This 66-year-old nonsmoking, HIV-negative woman had Tarui's disease diagnosed in 1997. Medical history had started in early childhood with febrile convulsions, which resolved without therapy. In 1977, simple partial seizures had begun, manifesting as aura with severe diffuse headache and the sensation of having a butterfly in the right ear, followed by aphasia and right-sided hemiparesis over 1 or 2 days. Conventional electroencephalogram showed diffuse slowing with right hemispheric predominance and a nonspecific focus on the left side. Cerebral angiography and pneumoencephalography were uninformative. Carbamazepine therapy stopped seizures completely and was discontinued after 1 year. In February 1982, pain in the right calf was interpreted as deep venous thrombosis, despite normal findings on phlebography. In September 1982, after arthroscopy was done because of a right knee joint effusion, chest pain and dyspnea occurred but resolved spontaneously. Despite normal results of perfusion scintigraphy of the l ungs and lower limb phlebography, pulmonary embolism was suspected, and phenprocumon therapy was begun. Chest pain frequently recurred, mainly during the night and could mostly be relieved with nitroglycerin. In 1983, muscle cramps of both calves occurred and progressed to the thighs and forearms during the following year. In 1983, creatine kinase (CK) and lactate dehydrogenase (LDH) levels were found to be elevated for the first time. Despite normal results of clinical cardiologic and pulmonary investigations, normal findings on ECG, and normal CK isoenzyme MB, chest pain was interpreted as myocardial infarction. The CK and LDH values remained elevated thereafter. Vertigo prompted a second cerebral angiography in 1984, and results were normal. In 1986, cramps began to affect all muscles, becoming more intense during the summer. In 1988, findings on clinical cardiologic examination, ECG, and coronary angiography were again normal. Bicycle ergometry showed no abnormality, but it had to be stopped at 75% becaus e of chest pain. Right ventriculography in 1990 was uninformative. In March 1993, the patient spontaneously fell from a chair without losing consciousness. This incident was interpreted as a transitory ischemic attack or seizure, since neurologic investigations were unremarkable (Table 1). Also in 1993, results of transthoracic echocardiography were normal (Table 1), but ultrasonography of the abdomen revealed a solitary liver cyst and cholecystolithiasis. In 1994, the patient began having recurrent double vision, and low-voltage EGG was recorded for the first time.

Cardiologic investigations in 1996 revealed normal clinical findings, low-voltage EGG,, slight left ventricular hypertrophy, enlarged left atrium, diastolic dysfunction, unremarkable bicycle ergometry until it had to be stopped at 98% because of dyspnea and muscle weakness, and normal results of radionuclide ventriculography, thallium perfusion scintigraphy, and coronary angiography (Table 1). Neurologic investigations revealed double vision when looking to the right, slightly prolonged distal latencies of the right median and left peroneal nerves, myogenic electromyogram of the right brachial biceps and right anterior tibial muscles, flat serum lactate response to ischemic forearm exercise, normal results of lactate stress test, and nonspecific demyelinating lesions on cerebral magnetic resonance imaging, one in the white matter on the right side and one in the left internal capsule (Table 2). Biopsy specimens from the right lateral vastus muscle revealed increased glycogen storage and absence of PFK on bioc hemical stain. Except for elevated lactate dehydrogenase, search for hemolytic anemia was negative (normal red blood cell and reticulocyte counts and normal bilirubin value).

In January 1997, the patient was found to have an adenomatous goiter with normal thyroid function. In April 1999, a right knee prosthesis was implanted because of gonarthrosis and has subsequently required 5 revisions. In June 1999, the patient suddenly lost consciousness, fell down seven steps, and awoke after an undetermined length of time. No medical investigation followed this event. In July 2000, sudden headache, nausea, and vertigo with vomiting occurred shortly after she woke up in the morning and stopped spontaneously after 2 or 3 days. All neurologic investigations were uninformative. In March 2001, she had a fall from a stepladder that she could not explain. While for 19 years nocturnal and exertional anginal chest pain had been the predominant cardiac symptom, increasing exertional dyspnea, orthopnea, and inability to lie on the left side developed in early 2001. Beginning in mid 2001, she had progressive exercise intolerance without a second wind phenomenon.

Neurologic investigation in July 2001 revealed generally reduced tendon reflexes, slight central facial palsy on the right side, right-sided dysmetria, bradydiadochokinesia, and finger straddling bilaterally (Medical Research Council grade 4+). Nerve conduction studies of the right median and left peroneal nerves showed increased latency of the median nerve exclusively. Electromyography of the right biceps brachii muscle was myogenic, that of the right anterior tibial muscle was normal. Findings on cerebral MRI were unchanged from those in 1996 (Table 1). Nuclear magnetic resonance spectroscopy could not be done because of the right knee prosthesis. Since the history strongly suggested complex partial seizures, carbamazepine therapy was initiated.

Cardiologic investigations in July 2001 showed normal clinical examination and low-voltage EGG. Ambulatory 24-hour ECG revealed ectopic supraventricular tachycardia. An event-recorder showed no relationship between the neurologic symptoms and the rhythm abnormalities. Echocardiography revealed a normal-sized left ventricle with good systolic function and thickening of the left ventricular myocardium (Table 2). The mitral valve was slightly thickened and showed grade I mitral insufficiency with a central jet for the first time. The right heart chambers were normal. The transmitral flow pattern was unchanged (E/A ratio <1) (Table 2). Cardiac MRI confirmed the diagnosis of left ventricular wall thickening and enlargement of the left atrium (Figure). Enalapril was effective and phenprocumon was discontinued. Abdominal ultrasonography revealed steatosis. There was no anemia, pale or icteric mucosa, fever, or hepatosplenomegaly. Except for elevated LDH, there was no indication of hemolysis. The patient's mother, si ster, and one daughter, who also reported early fatigue and exercise myalgias, refused neurologic and cardiologic investigation.

DISCUSSION

Glycogenosis type VII (Tarui's disease) is due to lack of PFK, an enzyme of the Embden-Meyerhof pathway of glucose metabolism catalyzing the conversion of fructose 6-phosphate to fructose 1,6 biphosphate. (4) Phosphofructokinase is tetrameric under the control of 3 loci that encode for 3 distinct subunits (M, L, P). (5) Human muscle and liver express homotetrameric isozymes (M4, L4), while erythrocytes express homotetrameric (M4, L4) and heterotetrameric isozymes (M3L, M2L2, M1L3). (6) Because only subunit M is expressed in the muscle, mutations in the corresponding gene result in total lack of PFK. (4) The gene for subunit M is located on chromosome [12.sub.q]3. (7) Mutations so far described in Tarui's disease are the common point mutation of the exon/intron 5 junction, (8,9) a cryptic splice site mutation within exon 15, (10) a 75-bp inframe deletion at the splice donor site of intron 5, (10) a nonsense mutation associated with retention of intron 10, (11) a single base deletion in exon 22, resulting in a frameshift mutation and premature stop codon, (10) a deletion of the 2003 C nucleotide, (12) a G1127A frameshift resulting in a 155nt retention of intron 13, (5) and an A-G change in intron 16. (5) These mutations have been identified in Japanese, Jewish, Italian, Canadian, Swiss, German, and Swedish patients. (5,10,13,14) Blocking of glycolysis by PFK deficiency not only prohibits the anaerobic formation of ATP, but also inhibits the oxidative ATP formation, manifesting as dramatically delayed recovery of Pcr after muscle loading on NMR spectroscopy. (12) Additionally, the oxygen delivery to the muscle may be impaired because of reduced 2,3 bisphosphoglycerate concentrations in the erythrocytes, resulting in increased affinity of hemoglobin for oxygen. (15)

Clinically, Tarui's disease is characterized by myopathy and compensated hemolytic anemia. (16) Half of the patients have myopathy and hemolytic anemia, whereas the other half exhibits only myopathy, only hemolysis, or no symptoms at all. (17) Myopathy may manifest itself as exercise intolerance, muscle cramps, weakness, due to muscle fiber necrosis, (9) reduced tendon reflexes, elevated serum levels of muscle enzymes, and abnormal ischemic forearm test. Pathomechanisms for myopathy are the impaired PFK activity and the intracellular glycogen storage, leading to displacement and compression of the contractile machinery. (18) There is also evidence for secondary oxidative impairment, showing reduced 02 uptake by exercising muscles. (19) Hemolytic anemia may manifest as elevated serum bilirubin, reticulocytes, or increased [Ca.sup.2++]-permeability due to absence of the M subunits in erythrocytes. (4,6,17,20) Exercise intolerance is explained by the blocked glycolysis and the initially decreased availability of free fatty acids ("out of wind" phenomenon). Increased fat oxidation after some time is made responsible for the "second wind" phenomenon, characterized by improved exercise capacity after an initial period of fatigue.' In single cases, central nervous system involvement, cardiac involvement, and insulin resistance have been described. (3,21) Cardiac manifestations include myocardial thickening and diastolic dysfunction. (2,4,22,23) Central nervous system manifestations previously described, are seizures, (22) mental retardation, and aplasia of the cerebellar vermis. (24) Storage of glycogen in central and peripheral axons, causing late-onset neuropathy, may be explained by M subunits as the major component of the cerebral PFK isozyme. (19)

Neurologic manifestations of the disease in our patient comprised focal epilepsy and myopathy, manifesting as muscle cramps, myalgias, double vision, weakness, reduced tendon reflexes, exercise intolerance, CK elevation, abnormal ischemic forearm test, myogenic EMG, and abnormal muscle biopsy. Progression of the neurologic abnormalities manifested as spreading muscle cramps, occurrence of reduced tendon reflexes, complex partial seizures, extrapyramidal signs, and weakness. The cause of epilepsy in the described patient remains speculative. Possibly, epilepsy was due to cerebral glycogen storage (not visible on cerebral MRI) or to vascular lesions, or it may have been of kryptogenic origin. Epilepsy has been previously described as a manifestation of Tarui's disease. (1,22) Whether febrile convulsions in childhood were already the first manifestation of the disease remains speculative. At least, the fall from the chair, the loss of consciousness with a consecutive fall down steps, and the fall from a stepladd er were interpreted as seizures.

Cardiac involvement initially manifested as chest pain, attributable either to cramps of the myocardium or the intercostal muscles. Pulmonary disease and coronary artery disease were repeatedly excluded. The next cardiac manifestation was low-voltage ECG, also attributed to intracellular glycogen storage. Glycogen may function as an isolator, allowing less current to reach the skin. The next cardiac manifestation was myocardial thickening, most likely due to glycogen storage, since there was no arterial hypertension, valve abnormality, or other cardiomyopathy. Diastolic dysfunction was attributed to glycogen storage, resulting in impaired myocardial relaxation. Glycogen storage was also made responsible for the thickened mitral valve, leading to mitral insufficiency and thus enlargement of the left atrium and atrial fibrillation, once noted in 1997. Enlargement of the left atrium, first noted in 1996, was not associated with mitral insufficiency at that time. Further increase in left atrial size and exertiona l dyspnea were attributed to mitral valve insufficiency and diastolic dysfunction. The response of chest pain to nitroglycerin remains unexplained. The goiter and steatosis were possibly due to accumulation of glycogen within the thyroid gland and liver. The delay in establishing the diagnosis in this case might be due to the mild symptoms, misinterpretation of cardiologic and neurologic manifestations, nonmeticulous clarification of symptoms, and unawareness of such a rare disorder.

CONCLUSION

Tarui's disease (glycogenosis type VII) may be associated with focal epilepsy, myopathy, and cardiomyopathy. Progression of cardiologic and neurologic abnormalities is slow, over a period of years. Adequate antiepileptic and cardiologic therapy may be helpful in these patients.

TABLE 1

Eight-Year Progression of Neurologic Involvement

                          1993    1996      2001

Complex partial seizures  No      No        Yes
Double vision             No      Yes       No
Exercise intolerance      No      No        Yes
Tendon reflexes           Normal  Normal    Decreased
Weakness                  No      No        Yes
Bradydiadochokinesia      No      No        Yes
Dysmetria                 No      No        Yes
Isehemic forearm test     ND      Abnormal  ND
Lactate stress test       ND      No        ND
Nerve conduction studies  ND      IDL       IDL
Electromyography          ND      Myogenic  Myogenic
Cerebral MRI              ND      Lacunas   Lacunas

ND = Not done, IDL = increased distal latencies, MRI = magnetic
resonance imaging.

TABLE

Eight-Year Progression of Cardiac Involvement

                                      1993      1996

Clinical cardiologic examination     Normal    Normal
Eelectrocardiogram                   Normal    Low-voltage
Ambulatory 24-hour electromyography  Not done  Not done

Ergometry                            Normal    Normal
Posterior wall thickness             Normal    13 mm
Septum thickness                     Normal    13 mm
E/A ratio                            Normal    <1
Mitral insufficiency                 No        No
Atrial diameter                      Normal    47 mm
Thickened mitral valve               No        No
Diastolic dysfunction                No        Yes
Radionuclide ventriculography        Normal    Normal
Thallium perfusion scintigraphy      Not done  Normal
Coronary angiography                 Normal    Normal

                                        2001

Clinical cardiologic examination     Normal
Eelectrocardiogram                   Low -voltage
Ambulatory 24-hour electromyography  Supraventricular
                                     tachycardia
Ergometry                            Not done
Posterior wall thickness             15 mm
Septum thickness                     15 mm
E/A ratio                            <1
Mitral insufficiency                 Yes
Atrial diameter                      53 mm
Thickened mitral valve               Yes
Diastolic dysfunction                Yes
Radionuclide ventriculography        Not done
Thallium perfusion scintigraphy      Not done
Coronary angiography                 Not done

References

(1.) Lin HC, Young C, Wang PJ, et al: Muscle phosphofructokinase deficiency (Tarui's disease): report of a case. J Formos Med Assoc 1999; 98:205-208

(2.) Amit R, Bashan N, Abarbanel JM, et al: Fatal familial infantile glycogen storage disease: multisystem phosphofructokinase deficiency. Muscle Nerve 1992; 15:455-458

(3.) Stollberger C, Finsterer J, Bittner R: Angina for 14 years. Lancet 1997; 349:1292

(4.) Vissing J, Galbo H, Haller RG: Paradoxically enhanced glucose production during exercise in humans with blocked glycolysis caused by muscle phosphofructokinase deficiency. Neurology 1996; 47:766-771

(5.) Nichols RC, Rudolphi O, Ek B, et al: Glycogenosis type VII (Tarui disease) in a Swedish family: two novel mutations in muscle phosphofructokinase gene (PFK-M) resulting in intron retentions. Am J Hum Genet 1996; 59:59-65

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

(7.) Howard TD, Akots G, Bowden DW: Physical and genetic mapping of the muscle phosphofructokinase gene (PFKM): reassignment to human chromosome 12q. Genomics 1996; 34:122-127

(8.) Argov Z, Barash V, Soffer D, et al: Late-onset muscular weakness in phosphofructokinase deficiency due to exon 5/intron 5 junction point mutation: a unique disorder or the natural course of this glycolytic disorder? Neurology 1944; 44:1097-1100

(9.) Sivakumar K, Vasconcelos O, Goldfarb L, et al: Late-onset muscle weakness in partial phosphofructokinase deficiency: a unique myopathy with vacuoles, abnormal mitochondria, and absence of the common exon 5/intron 5 junction point mutation, Neurology 1996; 46:1337-1342

(10.) Smith BF, Stedman H, Rajpurohit Y, et al: Molecular basis of canine muscle type phosphofructokinase deficiency. J Biol Chem 1996; 271:20070-20074

(11.) Vasconcelos O, Sivakumar K, Dalakas MC, 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. Proc Natl Acad Sci USA 1995; 92:10322-10326

(12.) Grehl T, Muller K, Vorgerd M, et al: Impaired aerobic glycolysis in muscle phosphofructokinase deficiency results in biphasic post-exercise phosphocreatine recovery in 31P magnetic resonance spectroscopy. Neuromuscul Disord 1998; 8:480-488

(13.) Raben N, Sherman JB: Mutations in muscle phosphofructokinase gene. Hum Mutat 1995; 6:1-6

(14.) Sherman JB, Raben N, Nicastri C, et al: Common mutations in the phosphofructokinase-M gene in Ashkenazi Jewish patients with glycogenosis VII and their population frequency. Am J Hum Genet 1994; 55:305-313

(15.) McCully K, Chance B, Giger U: In vivo determination of altered hemoglobin saturation in dogs with M-type phosphofructokinase deficiency. Muscle Nerve 1999; 22:621-627

(16.) Vorgerd M, Karitzky J, Ristow M, et al: Muscle phosphofructokinase deficiency in two generations. J Neurol Sci 1996; 141:95-99

(17.) Fujii H, Miwa S: Other erythrocyte enzyme deficiencies associated with non-haematological symptoms: phosphoglycerate kinase and phosphofructokinase deficiency. Baillieres Best Pract Res Clin Haematol 2000; 13:141-148

(18.) Massa R, Sancesario G, Bernardi G: Muscle phosphofructokinase deficiency. Neurology 1997; 49:899

(19.) Massa R, Lodi R, Barbiroli B, et al: Partial block of glycolysis in late-onset phosphofructokinase deficiency myopathy. Acta Neuropathol (Berl) 1996; 91:322-329

(20.) Fogelfeld L, Sarova-Pinchas I, Meytes D, et al: Phosphofructokinase deficiency (Tarui disease) associated with hepatic glucuronyltransferase deficiency (Gilbert's syndrome): a case and family study. Isr J Med Sci 1990; 26:328-333

(21.) Ristow M, Carlqvist H, Heblnck J: et al: Deficiency of phosphoftructo-1-kinase/muscle subtype in humans is associated with impairment of insulin secretory oscillations. Diabetes 1999; 48:1557-1561

(22.) DiMauro S, Tsujino S: Phosphofructokinase deficiency. Myology. Basic and Clinical. Engel AG, Franzini-Armstrong C (eds). New York, McGraw-Hill, 2nd Ed, 1994, pp 1563-1567

(23.) Haller RG, Lewis SF: Glucose-induced exertional fatigue in muscle phosphofructokinase deficiency. N Engl J Med 1991; 324:364-369

(24.) Pastoris O, Dossena M, Vercesi L, et al: Muscle phosphofructokinase deficiency in a myopathic child with severe mental retardation and aplasia of cerebellar vermis. Childs Neru Syst 1992; 8:237-241

KEY POINTS

* Phosphofructokinase deficiency (Tarui's disease) may manifest as mild symptoms of brain, muscle, and heart involvement.

* Tarui's disease may easily be misdiagnosed if there is no multidisciplinary diagnostic approach.

* The leading neurologic and cardiologic manifestations of Tarui's disease are seizures, muscle cramps, and chest pain, progressing only slightly over years.

From the Neurology Department, Neurological Hospital, Rosenhugel, and the Second Medical Department and Department of Radiology, Krankenanstalt Rudolfstiftung, Vienna, Austria.

Reprint requests to Josef Finsterer, MD, PhD, Postfach 348, 1180 Vienna, Austria.