Phosphofructokinase Deficiency

Synonyms include Tarui's disease, phosphofructokinase deficiency, PFK and glycogen storage disease (GSD) type VII.

Phosphofructokinase deficiency is one of the glycogen storage diseases. There is a congenital deficiency of an enzyme responsible for the breakdown of glycogen to glucose. It is classified as glycogen storage disease (GSD) type VII. It is also called Tarui's disease.

The enzyme deficiency results in the accumulation of glycogen in the tissues. There may be systemic consequences or there may be a limited number of tissues that are affected. Phosphofructokinase catalyzes the rate-limiting step in glycolysis. This is fructose-1-phosphate to fructose-1,6-diphosphate. Deficiency causes muscle pain and fatigue and weakness with exercise. It resolves with rest, but there is no specific treatment. It does not always progress to severe disability.

There are 3 variations:

• Infantile variety¹
• Classic variety
• Late onset type²

It is very rare but symptoms may be mild so that the true incidence may be higher because of lack of recognition. The fatal infantile variety has less than 10 reported cases. The late-onset form is the rarest. Many of those with late onset type admit to fatigue and muscle pain in their youth and it may be only the diagnosis that it late.

The disease is inherited as an autosomal recessive on chromosome 12³ but males outnumber females in reported cases.

It is more common in Ashkenazi Jews.⁴

• The presenting features are fatigue and pain with exercise. There may be nausea and vomiting too. This usually starts in childhood and is worse after moderate or intense exercise. Myoglobinuria presents as dark urine and severe muscle cramps may follow vigorous exercise.
• Carbohydrate-rich meals exacerbate the exercise intolerance. This is because glucose causes a reduction in circulating levels of free fatty acids that can act as an alternative substrate to glucose.⁵
• Patients with the late-onset form may have fixed muscle weakness.
• The infantile form presents in the 1st year of life with death before the 4th birthday. Blindness and psychomotor retardation may be the presenting symptoms of the infantile-onset type.
• The late-onset variant is manifest during later adulthood with progressive limb weakness but no myoglobinuria or cramps.

Fatal infantile variant

• Muscle weakness
• Cataracts
• Joint contractures

Classic and late-onset variety

• Muscle weakness, most pronounced after exercise
• Fixed limb weakness
• Muscle contractures
• Jaundice
• Joint pain

Symptoms are similar to McArdle's disease (Glycogen storage disease V) but more severe.

The differential diagnosis is between the various forms of glycogen storage diseases and other causes of myoglobinuria.

Blood

• Serum creatine kinase (CK) values usually are increased
• Lactic acid is not produced by exercise
• Bilirubin may be elevated. Check LFTs
• Fasting blood glucose should be checked. If it is low, there is risk if symptomatic hypoglycaemia
• Reticulocytosis may be present because of haemolysis

Urine

There may be myoglobinuria after exercise.

Imaging and Electrophysiology

• Brain scans in patients with the infantile-onset subtype show cortical atrophy and ventricular dilatation
• Electromyography (EMG) may show small motor potentials of short duration consistent with myopathic changes

Ischaemic Forearm Test

• Place a loose blood pressure cuff around the arm and place an antecubital cannula to sample blood
• Take blood for creatine kinase, ammonia, and lactate
• Inflate the cuff above systolic pressure and encourage the patient to squeeze an object at the rate of once or twice a second for 2 or 3 minutes although he may be unable to tolerate that duration
• Release the cuff and collect blood for creatine kinase, ammonia, and lactate immediately and at 5, 10, and 20 minutes
• Collect urine for myoglobin

Failure of the lactate level to rise is evidence of one of the glycogen storage diseases. Failure of the ammonia to rise suggests that exercise was not sufficiently brisk.

Histological Findings

Muscle biopsy gives typical results. Glycogen accumulates between myofibrils under the sarcolemma, as in McArdle's disease. An abnormal polysaccharide, unique to Tarui disease, may be found in older patients. Nonspecific myopathic changes occur. In infantile-onset Tarui disease there is little histological evidence of glycogen accumulation but measured glycogen is over twice the normal amount.

Glycogen storage diseases are caused by enzyme deficiency so that glycogen accumulates in tissues. Phosphofructokinase breaks down glycogen and deficiency causes ineffective glycolysis during exercise, resulting in pain, weakness, and cramps in the muscle. At least 14 types occur in the literature but only 4 cause significant muscle weakness.

• Type II, Acid maltase deficiency (Pompe's disease)
• Type III, Debranching enzyme deficiency (Forbes-Cori or Cori disease)
• Type V, Myophosphorylase deficiency (McArdle's disease)
• Type VII, Phosphofructokinase deficiency (Tarui disease)

• No specific treatment exists. The patient should avoid high-carbohydrate meals as they exacerbate exercise intolerance. There is increasing evidence that a high protein diet may slow progression of the disease.
• Vigorous exercise must be avoided as it causes myoglobinuria.
• No drugs are of any value.
• As this is a genetic disease, genetic counselling should be offered.
• Gene therapy may be possible for the future.

• Myoglobinuria can rarely lead to renal failure.
• Haemolysis can cause jaundice.
• Gallstones may require cholecystectomy.
• Elevated uric acid can cause gout.
• There may be involvement of heart muscle.⁶

Infantile variant

The original description of this type was of an infant with muscle weakness, seizures, cortical blindness, and corneal clouding who died of respiratory failure at 7 months. Two siblings born to consanguineous Bedouin parents also had cardiomyopathy and died in infancy.⁷ Others with the fatal infantile variant have painful joint contractures.

• The small number with the infantile variant have all died during early childhood.
• The classic and late-onset types are relatively mild disorders with minor lifestyle restrictions.

Prenatal detection is possible in families with identifiable mutations.