Pathophysiology^[2]

Phosphofructokinase (PFK) is needed for glycolysis. The enzyme deficiency results in the accumulation of glycogen in the tissues. The enzyme deficiency can also lead to increased uric acid production and therefore possible gout. There may be a compensated haemolytic anaemia.

PFK has muscle, liver and platelet subunits. In muscle tissue, it is only composed of muscle subunits but erythrocyte PFK is composed of both muscle and liver subunits. This means that in classic PFK deficiency, there is no PFK activity in muscle and about 50% activity in erythrocytes.

Epidemiology

• It is very rare and has been reported in approximately 100 patients worldwide.^[3]
• Symptoms may be mild in some people so there may be some cases that go unrecognised.^[2]
• Males appear to be affected more commonly than females.^[2]
• It is more common in Ashkenazi Jews.^[1][4]

Presentation^[2][5]

• Infantile-onset form:
  • The cases reported have presented under the age of 1 year.
  • Clinical features can include myopathy, psychomotor retardation, cataracts and joint contractures.
  • Death has occurred during childhood in all but one of the reported cases.^[6][7] There is a 2007 case report of a boy with phosphofructokinase (PFK) deficiency who presented, aged 3 days, with neonatal seizures and early infantile nonprogressive muscle weakness. He was gaining in his developmental milestones and his seizures were controlled on medication.^[8]
• Classic form:
  • Symptoms are usually first noticed in childhood.
  • There is exercise intolerance with pain, easy muscle fatigue, weakness and stiffness. Symptoms improve with rest.
  • Nausea and vomiting can occur after exercise.
  • If exercise intensity is increased, severe muscle cramps can occur.
  • Myoglobinuria can occur after intense exercise. This can rarely lead to acute kidney injury.
  • A compensated haemolysis may also be present and can lead to anaemia and sometimes jaundice.
  • Physical examination may be normal.
  • Gallstones (due to raised bilirubin) and gout may be other clinical features.
  • Neurological symptoms have been reported in one case study including complex partial seizures, diplopia, hyporeflexia, central facial palsy, and upper extremity weakness. The same patient had cardiac involvement (supraventricular tachycardia, thickened mitral valve, mitral valve insufficiency, enlarged left atrium, left ventricular hypertrophy, and diastolic dysfunction).^[9][10]
• Late-onset form:
  • This presents in adults as progressive muscle and limb weakness without cramps or myoglobinuria.^[11]

Differential diagnosis

• Symptoms may be similar to McArdle's glycogen storage disease but more severe.
• Consider other causes of muscle weakness and myoglobinuria.

Investigations

• Blood tests:
  • Serum creatine kinase is usually raised.
  • Fasting glucose: hypoglycaemia.
  • Uric acid: hyperuricaemia.
  • Bilirubin may be elevated; check LFTs (liver failure may occur).
  • FBC can show anaemia with a raised reticulocyte count.
  • Monitor renal function tests if myoglobinuria is present.
• Urinalysis:
  • There may be myoglobinuria after exercise.
• Imaging and electrophysiology:
  • Cortical atrophy and ventricular dilatation may be seen on brain imaging in the infantile form.
  • Electromyography (EMG) may show changes consistent with myopathy or may be normal.^[2][5]
• Ischaemic forearm test:^[2]
  • Inflate a blood pressure cuff around the arm to above systolic pressure.
  • Ask the patient to grasp an object in the hand of their same arm at a rate of 1-2 times per second for 2-3 minutes.
  • Take blood for creatine kinase, ammonia, and lactate as well as urinalysis for myoglobin 5, 10 and 20 minutes after inflating the cuff. (Also carry out these tests as a baseline just before the cuff is inflated.)
  • If lactate levels do not rise with ammonia levels, this is a positive test and is evidence of either Tarui's disease, Cori's disease (glycogen storage disease type III) or McArdle's disease (glycogen storage disease type V).
• Muscle biopsy:
  • Assay of phosphofructokinase (PFK) in muscle tissue shows reduced levels and can give a definitive diagnosis.^[2]

Management

• No specific treatment exists.
• The patient (or parents/carers) should be given information about the disorder and advised to avoid high-carbohydrate meals, as they can exacerbate exercise intolerance.^[2]
• There is evidence that a high-protein diet may improve muscle function and slow progression of the disease.^[5]
• Vigorous exercise should be avoided, as it causes myoglobinuria.^[2]
• Renal function should be monitored.
• Genetic counselling should be offered. Prenatal detection may be possible in families with identifiable mutations.^[2]
• Gene therapy may be possible for the future.

Complications

• Myoglobinuria and, rarely, renal failure.
• Haemolysis and jaundice.
• Gallstones.
• Gout.
• Heart muscle involvement.^[9]

Prognosis

• The few reported cases with the infantile variant have died during early childhood (with the exception of the recent case report which may be a different variant).^[2]
• Other types should be relatively mild disorders, only requiring minor lifestyle restrictions to avoid complications such as renal failure.^[2]