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.

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.

Normal Function

The ISCU 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). Specifically, the enzyme acts as a platform, or scaffold, for the assembly of these clusters. Fe-S 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.

Health Conditions Related to Genetic Changes

Myopathy with deficiency of iron-sulfur cluster assembly enzyme

At least two mutations in the ISCU gene have been found to cause myopathy with deficiency of iron-sulfur cluster assembly enzyme. The more common mutation, written as IVS5+382G>C, alters the way the gene's instructions are pieced together to produce the enzyme. Most affected individuals have this mutation in both copies of the ISCU gene in each cell. The other mutation, which has been identified in one family, replaces the amino acid glycine with the amino acid glutamate at position 50 in the enzyme (written as Gly50Glu or G50E). Affected individuals in this family have had the G50E mutation in one copy of the ISCU gene in each cell and the IVS5+382G>C mutation in the other copy of the gene. This combination of mutations causes a severe variant of the disorder characterized by progressive muscle weakness and wasting.

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 muscle weakness, pain, and the other features of myopathy with deficiency of iron-sulfur cluster assembly enzyme.

Other Names for This Gene

• HML
• hnifU
• iron-sulfur cluster scaffold homolog (E. coli)
• IscU
• IscU iron-sulfur cluster scaffold homolog
• ISCU_HUMAN
• ISU2
• MGC74517
• NIFU
• NifU-like N-terminal domain containing
• NIFUN
• nitrogen fixation cluster-like

Genomic Location

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.

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