Metabolic Myopathies

Adenylosuccinate Synthetase 1 (ADSS1) Myopathy

What is adenylosuccinate synthetase 1 myopathy?

Adenylosuccinate synthetase 1 (ADSS1) myopathy is an ultra-rare inborn error of metabolism-related neuromuscular disease. Characterized by a progressive myopathy, originally thought to be primarily distal, it arises from a mutation in the ADSS1 gene. This gene is responsible for the production of adenylosuccinate synthetase, a key enzyme involved with purine metabolism, that helps to maintain energy (adenosine triphosphate) levels within the striated muscle.

ADSS1 myopathy symptoms typically appear in early childhood, with disease progression generally starting in adolescence. ADSS1 myopathy affects both genders, with global incidence rates below 1 in 1,000,000 births. Most of the diagnosed patients are of Asian origin.

What are the symptoms of adenylosuccinate synthetase 1 myopathy?

ADSS1 myopathy generally presents as weakness in the distal muscles with reduced capacity for walking and running, reduced grip strength, and increased muscular fatigue. A common symptom of ADSS1 myopathy is difficulty with ascending stairs. There is significant proximal muscle involvement as the disease progresses. In later stages, approximately half of patients have trouble chewing and swallowing food, three quarters have difficulty breathing and one quarter of patients have cardiac symptoms.

At the microscopic level, muscles cells are infiltrated with lipids, myofibrillar aggregates and occasionally, nemaline rods (linked to metabolic stress), and have internalised nuclei. Moderate to marked variation is seen in fiber size with type 1 fiber atrophy.

What causes adenylosuccinate synthetase 1 myopathy?

In 2016, mutations of the ADSS1 gene were first conclusively linked to a distal myopathy. These mutations, located on chromosome 14, lead to reduced enzyme function. ADSS1 helps to support cellular ATP levels by stemming purine catabolism. ATP is important for muscle function and mass.

What is the progression of adenylosuccinate synthetase 1 myopathy?

The progressive nature of ADSS1 myopathy means that symptoms worsen over time, although the rate of progression is highly variable between patients. There is a worsening of muscle function over time, especially of strength and endurance. Eventually, everyday activities such as gentle walking and standing become impossible. Patients generally become wheelchair bound and have increasing difficulty with speech and feeding. Diminished heart and lung function leads to reduced life expectancy.

What is the status of research on adenylosuccinate synthetase 1 myopathy?

There is currently no cure or approved treatment for ADSS1 myopathy.

Ongoing research led by Cure ADSSL1 is making progress on a number of fronts, including:

• Better diagnosis to allow for earlier identification of at-risk individuals;
• Development of animal models of ADSS1 myopathy, both to improve understanding of the disease and to test possible treatments;
• Development of small-molecule therapeutics;
• Development of gene replacement therapy.