IllnessMitochondrial diseases, complex V deficiency; differential diagnosis

NGS +

Complex V is one of the five mitochondrial complexes involved in the oxidative phosphorylation process. Complex V deficiency (ATP synthase deficiency) can cause a variety of symptoms affecting different organs and systems, especially the nervous system and heart, which can be life-threatening in infancy. Patients grow slowly, are lethargic with muscle hypotonia and developmental delay due to lactic acidosis and eventually hyperammonemia causing encephalopathy, for example. In addition, a striking pattern of facial features and hypertrophic cardiomyopathy may be observed. Some patients present with a specific symptom combination of neuropathy, ataxia and retinitis pigmentosa (NARP), often with cognitive impairment and vision loss. Leigh syndrome may also be associated with early progressive loss of mental and motor abilities, usually leading to death after 2-3 years. Gene mutations that cause mitochondrial complex V deficiency impair either complex V formation or its function. Impaired oxidative phosphorylation leads to cell death in the nervous system, heart, liver, kidneys and skeletal muscle. The cell nuclear gene TMEM70 is most commonly mutated. When a mutation occurs in the mtDNA, sometimes only a portion of these molecules can carry the change, a so-called heteroplasmic state. The higher the proportion of mutated mtDNA the more severe the disease usually is. Nuclear mutations are inherited autosomal recessively, changes in mtDNA only 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: ATP synthase deficiency
• Mitochondrial complex V (ATP synthase) deficiency (ATP5D)
• Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1 (ATPAF2)
• Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (TMEM70)
• Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 (ATP5E)
• Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4 (ATP5A1)
• [No OMIM phenotype: ATP5B, ATP5C1, ATP5F1, ATO5G1-3, ATP5H-I, ATP5J-J2, ATP5L-L2, ATP5O, ATPAF1]