IllnessMitochondrial diseases, complex III deficiency; differential diagnosis

NGS +

Mitochondrial complex III deficiency (isolated CoQ cytochrome c reductase deficiency or ubiquinone cytochrome c oxidoreductase deficiency) can affect the brain, kidneys, liver, heart and skeletal muscles. Symptoms usually begin in infancy, but can occur later as well. The severity of the deficiency varies widely among affected individuals. Mildly affecteds tend to have myopathy and fatigue, especially exercise intolerance. Severely affected individuals have liver affection leading to liver failure, renal tubulopathy and encephalopathy with psychomotor retardation, movement problems, muscle hypotonia and communication difficulties. Some affected individuals have cardiomyopathy that can lead to heart failure, while most have lactic acidosis or ketoacidosis or hyperglycemia. The disease can be fatal in childhood, although individuals with mild signs and symptoms can survive into adolescence or adulthood. Mitochondrial complex III deficiency can be caused by mutations in one of several genes. The most commonly mutated genes are BCS1L and MT-CYB. Cytochrome b protein, encoded by the MT-CYB gene, is a component of complex III, and the protein produced by the BCS1L gene is critical for the formation of the complex. Complex III is one of several complexes that carry out the multistep process of oxidative phosphorylation. Most somatic cells contain thousands of mitochondria, each with one or more copies of mtDNA. These cells may have a mixture of mitochondria with mutant and non-mutant DNA (heteroplasmy). Mitochondrial complex III deficiency is usually inherited in an autosomal recessive manner, if caused by mutations in the MT-CYB gene inherited mitochondrially, in other cases it is not inherited but caused by somatic mutations in the MT-CYB gene. Since the diagnostic yield in mitochondrial diseases is in summary 70% or less, even with complete analysis of mtDNA and the corresponding nuclear genes, a negative molecular genetic test does not exclude the clinical diagnosis.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1224/

• Alias: Isolated CoQ-cytochrome c reductase deficiency
• Alias: Ubiquinone-cytochrome c oxidoreductase deficiency
• Bjornstad syndrome (BCS1L)
• GRACILE syndrome (BCS1L)
• Mitochondrial complex III deficiency, nuclear type 1 (BCS1L)
• Mitochondrial complex III deficiency, nuclear type 10 (UQRFS1)
• Mitochondrial complex III deficiency, nuclear type 2 (TTC19)
• Mitochondrial complex III deficiency, nuclear type 3 (UQCRB)
• Mitochondrial complex III deficiency, nuclear type 4 (UQCRQ)
• Mitochondrial complex III deficiency, nuclear type 5 (UQCRC2)
• Mitochondrial complex III deficiency, nuclear type 6 (CYC1)
• Mitochondrial complex III deficiency, nuclear type 7 (UQCC2)
• Mitochondrial complex III deficiency, nuclear type 8 (LYRM7)
• Mitochondrial complex III deficiency, nuclear type 9 (UQCC3)
• [No phenotypes: UQCC1, UQCC3, UQCR10, UQCR11]