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 Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates i ...

(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.Fullerton M, McFarland R, Taylor RW, Alston CL. The genetic basis of isolated mitochondrial complex II deficiency. Mol Genet Metab. 2020 Sep-Oct;131(1-2):53-65. doi: 10.1016/j.ymgme.2020.09.009. Epub 2020 Oct 3. PMID 33162331; PMCID: PMC7758838.

Signs and symptoms

Mitochondrial complex II deficiency affects the body's

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

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 The plantar reflex is a reflex elicited when the sole of the foot is stimulated with a blunt instrument. The reflex can take one of two forms. In healthy adults, the plantar reflex causes a downward response of the hallux (flexion). An upward re ...

, failure to thrive, muscle weakness, distal

amyotrophy Amyotrophy is progressive wasting of muscle tissues. Muscle pain is also a symptom. It can occur in middle-aged males with type 2 diabetes. It also occurs with motor neuron disease. Differential diagnosis The following are considered differenti ...

(muscle wasting of the limbs), and

developmental regression Developmental regression is when a child who has reached a certain developmental stage begins to lose previously acquired milestones. It differs from developmental delay in that a child experiencing developmental delay is either not reaching devel ...

(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 Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. It ...

(as opposed to mitochondrial DNA), with both

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

recessive and dominant inheritance. Most pathogenic mutations for CII deficiency occur on

SDHA Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the ''SDHA'' gene. This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respi ...

SDHAF1 Succinate dehydrogenase complex assembly factor 1 (SDHAF1), also known as LYR motif-containing protein 8 (LYRM8), is a protein that in humans is encoded by the ''SDHAF1,'' or ''LYRM8,'' gene. SDHAF1 is a Chaperone (protein), chaperone protein invo ...

, 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 Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial Cell (biology), cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that ...

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 Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...

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. Ürey BC, Ceylan AC, Çavdarlı B, Çıtak Kurt AN, Köylü OK, Yürek B, Kasapkara ÇS. Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report. Mol Syndromol. 2023 Apr;14(2):171-174. doi: 10.1159/000527538. Epub 2023 Jan 13. PMID 37064335; PMCID: PMC10090973.

References

{{reflist Rare diseases Genetic diseases and disorders Mitochondrial diseases Autosomal recessive disorders