Myoadenylate deaminase deficiency

Myoadenylate Deaminase Deficiency

Myoadenylate deaminase deficiency (MADD) is a metabolic disorder that affects skeletal muscle function. It is characterized by a deficiency in the enzyme myoadenylate deaminase, which plays a crucial role in the purine nucleotide cycle, particularly during muscle exertion. This condition can lead to exercise intolerance, muscle pain, and cramps.

Pathophysiology

Myoadenylate deaminase, also known as AMP deaminase, is an enzyme that catalyzes the deamination of adenosine monophosphate (AMP) to inosine monophosphate (IMP) and ammonia. This reaction is part of the purine nucleotide cycle, which is important for maintaining the energy balance in muscle cells during periods of high energy demand, such as exercise.

In individuals with myoadenylate deaminase deficiency, the lack of functional enzyme impairs the conversion of AMP to IMP, leading to an accumulation of AMP and a subsequent decrease in the availability of ATP, the primary energy carrier in cells. This results in reduced energy production during muscle contraction, causing symptoms such as muscle fatigue and pain.

Genetics

Myoadenylate deaminase deficiency is most commonly inherited in an autosomal recessive manner. The condition is associated with mutations in the AMPD1 gene, which encodes the myoadenylate deaminase enzyme. The most common mutation is a nonsense mutation, c.34C>T (p.Gln12Ter), which leads to a premature stop codon and a truncated, non-functional enzyme.

Clinical Presentation

Symptoms of myoadenylate deaminase deficiency can vary widely among affected individuals. Common symptoms include:

- Exercise intolerance - Muscle pain (myalgia) - Muscle cramps - Fatigue

Some individuals may remain asymptomatic, while others experience significant limitations in physical activity.

Diagnosis

Diagnosis of myoadenylate deaminase deficiency typically involves a combination of clinical evaluation, biochemical testing, and genetic analysis. Key diagnostic steps include:

- Muscle biopsy: Histochemical staining for myoadenylate deaminase activity can reveal reduced or absent enzyme activity in muscle tissue. - Genetic testing: Identification of mutations in the AMPD1 gene confirms the diagnosis. - Exercise testing: Measurement of ammonia and lactate levels during exercise can help assess the metabolic response of muscles.

Management

There is currently no cure for myoadenylate deaminase deficiency. Management focuses on alleviating symptoms and improving quality of life. Strategies include:

- Exercise modification: Tailoring exercise programs to avoid activities that trigger symptoms. - Dietary adjustments: Some patients may benefit from a diet rich in carbohydrates to optimize energy availability. - Supportive therapies: Physical therapy and occupational therapy can help maintain muscle function and mobility.

Epidemiology

Myoadenylate deaminase deficiency is considered one of the most common metabolic myopathies, with a prevalence that varies among different populations. It is estimated to affect approximately 1-2% of the general population, with a higher prevalence in individuals of European descent.

Also see

- Metabolic myopathy - Purine metabolism - AMP deaminase - Exercise intolerance