Simply Stated: Introduction to CIAO1-Related Neuromuscular Disorder

CIAO1-related neuromuscular disorder is an inherited condition that was first reported on in late 2023. It is caused by variants in the CIAO1 gene and primarily affects muscle function, though many affected people also experience problems with the nervous system. Much about the symptoms and progression of this newly discovered condition remains to be defined. The exact prevalence is also unknown, but it is currently considered an ultra-rare disorder.

Cause of CIAO1-related neuromuscular disorder

This disorder is genetic and inherited in an autosomal recessive pattern, meaning both copies of the CIAO1 gene must be affected in order to develop the disorder.

The CIAO1 gene is involved in the assembly of iron-sulfur (Fe-S) clusters, which are critical components for the proper functioning of many cellular enzymes. Defects in this gene compromise the functions of these enzymes, thereby disrupting important cellular processes, including DNA replication, RNA processing, and mitochondrial metabolism and energy production. These disruptions lead to the muscle and nervous system symptoms seen in people with CIAO1-related neuromuscular disorder.

Symptoms of CIAO1-related neuromuscular disorder

Only a small number of people with CIAO1-related neuromuscular disease have been described to date. In most cases, symptoms begin in early childhood or adolescence. Though symptoms and severity vary, reported cases show some combination of following:

·       Muscle involvement (most common)

o   Progressive weakness of the shoulders, hips, and trunk (often proximal > distal)

o   Delayed motor milestones

o   Low muscle tone (hypotonia)

o   Fatigue and exercise intolerance

o   Facial, swallowing (bulbar), and sometimes breathing muscle weakness

o   Elevated muscle enzymes (e.g., creatine kinase) and signs of muscle and mitochondrial dysfunction on testing

·       Nervous system involvement

o   Learning and cognitive difficulties

o   Neurobehavioral differences in some individuals

o   In a subset, iron accumulation in deep brain regions on imaging

·       Additional features (variable)

o   Macrocytic anemia

o   Gastrointestinal symptoms

To learn more about what is currently known about this condition, the following publications may be helpful:

• JCI article from Maio, et al., 2024
• 2026 MDA Conference Poster #329T by Bach, et al. 2026
• 2026 MDA Conference Poster #T371 by Bach, et al. 2026

Diagnosis of CIAO1-related neuromuscular disorder

Diagnosis of CIAO1-related neuromuscular disorder can be challenging, as symptoms may overlap with other neuromuscular or mitochondrial disorders. Evaluation is likely to involve a combination of clinical, laboratory, and genetic assessments. Genetic testing to identify disease-causing variants in the CIAO1 gene can help confirm the diagnosis.

Current management of CIAO1-related neuromuscular disorder

There are no disease-specific therapies currently approved for CIAO1-related neuromuscular disorder. Current management is supportive and similar to that of other neuromuscular conditions, focusing on:

·       Physical and occupational therapy to maintain strength and mobility

·       Respiratory monitoring if weakness progresses

·       Nutritional and metabolic support as needed

·       Symptom-based care tailored to individual needs0

Evolving research and treatment landscape

Understanding of the natural history and treatment of CIAO1-related neuromuscular disease is very limited given its recent identification. Ongoing research is preclinical and focused on:

·       Defining the clinical spectrum and progression of the disorder in affected individuals

·       Understanding the mechanisms that cause disease (e.g., How problems with iron-sulfur (Fe-S) cluster assembly contribute to disease)

·       Identifying potential treatment targets to guide development of future therapies

As knowledge of the condition advances, earlier diagnosis and new therapeutic strategies may become possible.

MDA’s work to further cutting-edge CIAO1-related neuromuscular disorder research

As part of MDA’s broader mission to support people living with neuromuscular diseases, CIAO1-related neuromuscular disorder was recently added to the MDA disease portfolio, reflecting its impact and MDA’s commitment to supporting individuals and families affected by this condition. Through recognition and investments in research from MDA, partner advocacy groups, and the National Institutes of Health (NIH), efforts to better understand CIAO1-related neuromuscular disorder are advancing, offering hope for better management and future treatments for people living with this condition.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about CIAO1-related neuromuscular disorder, open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.