IllnessMitochondrial diseases, complex IV deficiency; differential diagnosis

NGS +

Complex IV is one of the five mitochondrial complexes involved in the oxidative phosphorylation process. Complex IV deficiency, or cytochrome c oxidase deficiency, is a genetic disorder that can affect the skeletal muscle, the heart, the brain or the liver via reduced energyin the process known as oxidative phosphorylation for energy production. Symptoms usually begin before age 2 or may occur later in mildly affected individuals. The severity varies widely among affected individuals, even within a family. People who are mildly affected tend to have myopathy and hypotonia without other associated health problems. Severely affected individuals have problems in multiple body systems, often including severe encephalomyopathy. 25% of these patients show hypertrophic cardiomyopathy or hepatomegaly, which can lead to liver failure. Most affected individuals suffer from lactic acidosis. Many people with complex IV deficiency have Leigh syndrome with mental function loss, movement problems, hypertrophic cardiomyopathy, nutritional problems and brain abnormalities. Complex IV deficiency is one of the many causes of Leigh syndrome, with patients often not surviving childhood, although some affected individuals live into adolescence or adulthood with mild symptoms. Mutations in more than 20 genes are the cause of complex IV deficiency. Most of these genes are located in nuclear DNA. These mutations affect components of the cytochrome c oxidase enzyme complex, which is responsible for one of the final steps in oxidative phosphorylation. Many other proteins are additionally involved in the assembly of these holoenzymes, one of the main causes of said deficiency. Provided a mutation occurs in the mtDNA, sometimes only a portion of these mt-DNA rings can carry the change, a so-called heteroplasmic state. The higher the proportion of mutated mtDNA molecules, the more severe the disease usually is. Nuclear mutations are inherited in an autosomal recessive manner, and changes in mtDNA are passed on maternally. 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: Cytochrom-c-Oxidase-Mangel
• Charcot-Marie-Tooth disease, recessive intermediate D (COX6A1)
• Charcot-Marie-Tooth disease, type 4K (SURF1)
• Exocrine pancreatic insufficiency, dyserythropoietic anemia + calvarial hyperostosis (COX4I2)
• Leigh syndrome (SQOR)
• Linear skin defects with multiple congenital anomalies 2 (COX7B)
• Mitochondrial complex IV deficiency (COX8A)
• Mitochondrial complex IV deficiency, nuclear type 1 (SURF1)
• Mitochondrial complex IV deficiency, nuclear type 10 (COX14)
• Mitochondrial complex IV deficiency, nuclear type 11 (COX20)
• Mitochondrial complex IV deficiency, nuclear type 12 (PET100)
• Mitochondrial complex IV deficiency, nuclear type 13 (COA6)
• Mitochondrial complex IV deficiency, nuclear type 16 (COX4I1)
• Mitochondrial complex IV deficiency, nuclear type 17 (COA8)
• Mitochondrial complex IV deficiency, nuclear type 2 (SCO2)
• Mitochondrial complex IV deficiency, nuclear type 20 (COX5A)
• Mitochondrial complex IV deficiency, nuclear type 21 (NDUFA4)
• Mitochondrial complex IV deficiency, nuclear type 3 (COX10)
• Mitochondrial complex IV deficiency, nuclear type 4 (SCO1)
• Mitochondrial complex IV deficiency, nuclear type 5 [French-Canadian] (LRPPRC)
• Mitochondrial complex IV deficiency, nuclear type 6 (COX15)
• Mitochondrial complex IV deficiency, nuclear type 7 (COX6B1)
• Mitochondrial complex IV deficiency, nuclear type 8 (TACO1)
• Mitochondrial complex IV, deficiency, nuclear type 9 (COA5)
• Myopia 6 (SCO2)
• Spinocerebellar ataxia, AR, with axonal neuropathy 3 (COA7)