Mitochondrial complex II deficiency



Mitochondrial complex II deficiency, also called CII deficiency, is an extremely rare mitochondrial disease caused by deficiency of mitochondrial complex II, also known as Succinate dehydrogenase (SDH). SDH plays a key role in cellular respiration within the tricarboxylic acid (TCA) cycle and the electron transport chain. As of 2020, about sixty-one cases have been documented in literature.

Signs and symptoms
Mitochondrial complex II deficiency affects the body's mitochondria and can have a variety of presentations. In some cases, the brain, heart, liver, kidneys, and muscles are affected, while in other cases, only the heart and muscles are affected. The condition can present differently among different individuals, even those in the same family, but symptoms can largely be separated into two categories. In early presentation, often caused by homozygous or compound heterozygous mutations of SDHA, common symptoms include the Babinski sign, failure to thrive, muscle weakness, distal amyotrophy (muscle wasting of the limbs), and developmental regression (loss of developmental milestones). In later (Adult) presentation, often caused by heterozygous mutations of SDHA, common symptoms include being easy to fatigue, double vision and other vision problems, and exercise intolerance.

Causes
CII deficiency is a genetic disorder caused by Nuclear DNA (as opposed to mitochondrial DNA), with both autosomal recessive and dominant inheritance. Most pathogenic mutations for CII deficiency occur on SDHA or SDHAF1, but other pathogenic mutations for CII are known for SDHB and SDHD. SDHA is the only SDHx gene reported to date in which dominant pathogenic variants have been identified although most affected individuals harbour either homozygous or compound heterozygous pathogenic variants, consistent with autosomal recessive inheritance.

Diagnosis
The most effective way to diagnose CII deficiency is by measuring the activity of complex II in the muscles, however, there is no clear correlation between residual complex II activity and severity or clinical outcome.

Prognosis
The prognosis can vary wildly for CII deficiency: The disease is generally less severe in those who are heterozygous for the mutation, present later, and have less of a deficiency (typically measured in a muscle biopsy). Those presenting with Leigh syndrome or greater neurological involvement have worse outcomes. In severe cases where multiple organ systems are affected, death can occur in early life due to multisystem failure.

There is no cure for complex II deficiency, though some reported patients showed clinical improvement following riboflavin therapy.