Phosphofructokinase deficiency

Synonyms: Tarui's disease, glycogen storage disease type VII, muscle phosphofructokinase deficiency

What is phosphofructokinase deficiency?

Phosphofructokinase (PFK) deficiency is a glycogen storage disorder (GSD). It is rare and is inherited as an autosomal recessive disorder. There is a mutation in the gene encoding muscle PFK on chromosome 12.¹

There is also reduced activity of red cell PFK. The main clinical features include exercise intolerance, muscle cramping, exertional myopathy, compensated haemolysis and myoglobinuria.¹ There are three subtypes:

• Infantile-onset (a few rare cases have been reported).

• Classic (most common).

• Late-onset.

What is phosphofructokinase? (Pathophysiology)

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.

How common is phosphofructokinase deficiency? (Epidemiology)

• It is very rare and has been reported in approximately 100 patients worldwide.²

• The overall incidence of glycogen storage disorders is estimated as 1 per 20,000-43,000 live births.³

• Symptoms may be mild in some people so there may be some cases that go unrecognised.

• Males appear to be affected more commonly than females.

• It is more common in Ashkenazi Jews.¹

Phosphofructokinase deficiency symptoms (presentation)⁴

Infantile-onset form²

• The cases reported have presented under the age of 1 year.

• Clinical features can include myopathy, psychomotor impairment, cataracts and joint contractures.

• Death usually occurs during childhood.

• There is a 2007 case report of a boy with PFK deficiency who presented, aged 3 days, with neonatal seizures and early infantile non-progressive muscle weakness. He was gaining in his developmental milestones and his seizures were controlled on medication.⁵

Classic form

• Symptoms are usually first noticed in childhood.

• There is exercise intolerance with muscle 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 haemolytic 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).⁶

Late-onset form

• This presents in adults as progressive muscle and limb weakness without cramps or myoglobinuria.

Differential diagnosis

• Symptoms may be similar to McArdle's glycogen storage disease but more severe.

• Consider other causes of muscle weakness and myoglobinuria.

Investigations⁴

• 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.

• Muscle biopsy:

  • Assay of PFK in muscle tissue shows reduced levels and can give a definitive diagnosis.

Phosphofructokinase deficiency treatment⁴

• 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.

• A healthy diet should be encouraged. There is evidence that a high-protein diet may improve muscle function and slow progression of the disease.

• One study found a long-term effect of a ketogenic diet, with an improvement of muscle symptoms, breathing, exercise performance and oxygen uptake.⁷

• Anaerobic exercise should be avoided.

• Renal function should be monitored.

• Genetic counselling should be offered. Prenatal detection may be possible in families with identifiable mutations.

• Gene therapy may be possible for the future.

Complications

• Myoglobinuria and (rarely) acute kidney injury.

• Haemolysis and jaundice.

• Gallstones.

• Gout.

• Cardiomyopathy and heart valve involvement.⁶

Prognosis

• The infantile variant generally has a very poor prognosis with death in infancy and early childhood.²

• However there is a case report of a boy with PFK deficiency who presented when 3 days old with neonatal seizures and early infantile non-progressive muscle weakness but went on to attain normal developmental milestones and his seizures were controlled on medication.⁵

• The prognosis for the other variants is usually very good but weakness and stiffness invariably appear in muscle groups subjected to vigorous or prolonged exertion.³