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 in the purine nucleotide cycle (PNC), that helps to maintain energy (adenosine triphosphate) levels within the muscle.

ADSS1 myopathy usually onsets early in adolescence, although onset can be variable and as early as childhood. ADSSM1 affects both genders, with global incidence rates below 1 in 1,000,000 births.

What are the symptoms of adenylosuccinate synthetase 1 myopathy?

ADSSM1 generally presents as weakness in the distal muscles, characterized by reduced capacity for walking and running, reduced grip strength, and increased muscular fatigue. A common symptom of ADDS1 myopathy is difficulty with ascending stairs. There is significant proximal muscle involvement as the disease progresses. In later stages of the disease, approximately half of patients have trouble chewing and swallowing food, three quarters have difficulty breathing and one quarter of patients.

At the microscopic level, muscles cells are infiltrated with lipids, myofibrillar aggregates and occasionally, nemaline rods (linked to metabolic stress), and have internalised nuclei.

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 an improperly constructed enzyme which interrupts the PNC. The PNC is a system which transfers the building blocks of energy from the food we eat, into cells, allowing them to build new cells, and create energy.

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 (generally between 50-60 years age).

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 metabolite replenishment;
• Development of gene therapies.