Myopathy with deficiency of iron-sulfur cluster assembly enzyme

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Myopathy with deficiency of iron-sulfur cluster assembly enzyme is an inherited disorder that primarily affects muscles used for movement (skeletal muscles). This condition does not usually affect other types of muscle, such as the heart (cardiac) muscle.

From early childhood, affected individuals experience extreme fatigue in response to physical activity (exercise intolerance). Mild exertion results in a rapid heartbeat (tachycardia), shortness of breath, and muscle weakness and pain. However, people with this condition typically have normal muscle strength when they are at rest.

Prolonged or recurrent physical activity causes more severe signs and symptoms, including a breakdown of muscle tissue (rhabdomyolysis). The destruction of muscle tissue releases a protein called myoglobin, which is processed by the kidneys and released in the urine (myoglobinuria). Myoglobin causes the urine to be red or brown. This protein can also damage the kidneys, in some cases leading to life-threatening kidney failure.

In most affected individuals, the muscle problems associated with this condition do not worsen with time. However, at least two people with a severe variant of this disorder have experienced progressive muscle weakness and wasting starting in childhood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Myopathy with deficiency of iron-sulfur cluster assembly enzyme is caused by mutations in the ISCU gene. This gene provides instructions for making a protein called the iron-sulfur cluster assembly enzyme. As its name suggests, this enzyme is involved in the formation of clusters of iron and sulfur atoms (Fe-S clusters). These clusters are critical for the function of many different proteins, including those needed for DNA repair and the regulation of iron levels. Proteins containing Fe-S clusters are also necessary for energy production within mitochondria, which are the cell structures that convert the energy from food into a form that cells can use.

Mutations in the ISCU gene severely limit the amount of iron-sulfur cluster assembly enzyme that is made in cells. A shortage of this enzyme prevents the normal production of proteins that contain Fe-S clusters, which disrupts a variety of cellular activities. A reduction in the amount of iron-sulfur cluster assembly enzyme is particularly damaging to skeletal muscle cells. Within the mitochondria of these cells, a lack of this enzyme causes problems with energy production and an overload of iron. These defects lead to exercise intolerance and the other features of myopathy with deficiency of iron-sulfur cluster assembly enzyme.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

This condition has been reported in several families of northern Swedish ancestry.

Understanding terms used in the source

These definitions explain medical words used above. A definition is not evidence that another condition is present, and it does not predict how a symptom will develop. Ask the clinician which terms apply to the actual examination or test result.

Exercise intolerance

A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender.

Rhabdomyolysis

Breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream.

Progressive

Applies to a disease manifestation that increases in scope or severity over the course of time, i.e., that worsens with age.

Tachycardia

A rapid heartrate that exceeds the range of the normal resting heartrate for age.

Prolonged

Applied to an abnormality whose duration is extended over a longer period of time than is expected or usual (e.g., prolonged fever lasts longer than one usually sees with an infection).

Which doctor should you see?

The suggested department for discussing Myopathy with deficiency of iron-sulfur cluster assembly enzyme is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Myopathy with deficiency of iron-sulfur cluster assembly enzyme. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.