Mitochondrial disorders are caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that affect mitochondrial function. These conditions involve impaired energy production due to defects in the mitochondrial respiratory chain (oxidative phosphorylation), leading to multi-system involvement.

• Disorders Caused by mtDNA Mutations
  These are typically inherited maternally since mtDNA is passed from mother to child.
  • Point Mutations in mtDNA
    • MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes.
    • MERRF: Myoclonic Epilepsy with Ragged-Red Fibers.
    • LHON: Leber Hereditary Optic Neuropathy.
    • NARP: Neuropathy, Ataxia, and Retinitis Pigmentosa.
    • Pearson Syndrome: Bone marrow failure and pancreatic dysfunction.
    • Deafness and Diabetes (MIDD): Associated with the m.3243A>G mutation.
    • Leigh Syndrome (mtDNA-associated): A progressive neurodegenerative disorder.
  • Large-Scale Rearrangements in mtDNA
    • Kearns-Sayre Syndrome (KSS): Progressive external ophthalmoplegia, heart block, and pigmentary retinopathy.
    • Chronic Progressive External Ophthalmoplegia (CPEO): Progressive muscle weakness affecting eye movement.
    • Pearson Syndrome: Overlaps with KSS but involves bone marrow and pancreatic dysfunction.
  • mtDNA Depletion Syndromes
    Conditions caused by reduced mtDNA copy numbers in cells, often linked to nuclear gene mutations affecting mtDNA maintenance
• Disorders Caused by Nuclear DNA Mutations
  These often follow autosomal recessive, autosomal dominant, or X-linked inheritance patterns.
  • Leigh Syndrome (Nuclear DNA Mutations)Caused by defects in nuclear genes involved in oxidative phosphorylation, such as SURF1, PDHA1, NDUFS4, and others.
  • Mitochondrial DNA Maintenance Disorders
    • Alpers-Huttenlocher Syndrome: POLG mutations.
    • Mitochondrial DNA Depletion Syndromes (MDDS):
    • TK2-related myopathy.
    • DGUOK-related hepatocerebral syndrome.
    • RRM2B-related encephalopathy.
    • SUCLA2- and SUCLG1-related encephalomyopathies.
    • PEO and mtDNA deletion syndromes: Associated with mutations in TWNK, POLG, and OPA1.
  • Disorders of the Mitochondrial Respiratory Chain
    • Complex I Deficiency: Mutations in genes like NDUFS1, NDUFV1, and others.
    • Complex II Deficiency: Linked to SDHA, SDHB, SDHC, and SDHD mutations.
    • Complex III Deficiency: Caused by mutations in genes like BCS1L or UQCRB.
    • Complex IV Deficiency (Cytochrome c Oxidase Deficiency):
      • SURF1 mutations or assembly factor defects like SCO2.
    • Complex V Deficiency (ATP Synthase Deficiency):
      • Mutations in ATP5A1, ATP5E, etc.
  • Coenzyme Q10 Deficiency
    • Caused by mutations in COQ2, COQ6, PDSS2, or ADCK3.
    • Symptoms include muscle weakness, kidney disease, and cerebellar ataxia.
  • Disorders of Mitochondrial Protein Translation
    • Leigh Syndrome (e.g., GFM1, TSFM)
    • Combined oxidative phosphorylation disorders.
  • Pyruvate Metabolism Disorders
    • Pyruvate Dehydrogenase Complex Deficiency: Mutations in PDHA1, PDHX, etc.
  • Disorders of Iron-Sulfur Cluster Assembly
    • Friedreich’s Ataxia: Caused by mutations in the FXN gene.
    • Multiple Mitochondrial Dysfunction Syndromes (MMDS): Linked to NFU1, BOLA3, IBA57, etc.
  • Disorders of Mitochondrial Dynamics
    • Charcot-Marie-Tooth Disease Type 2A: Associated with mutations in MFN2.
    • Optic Atrophy Type 1: Caused by mutations in OPA1.
  • Other Nuclear Gene Disorders
    • Barth Syndrome: Mutations in TAZ affecting mitochondrial membrane structure.
    • Leigh-like Syndrome: Caused by SURF1 or other assembly factor mutations.
    • Sengers Syndrome: AGK gene mutation; presents with cataracts, myopathy, and cardiomyopathy.
  • Other Syndromes with Secondary Mitochondrial Dysfunction
    These disorders affect mitochondrial function indirectly.
    • Wilson’s Disease
    • Lysosomal Storage Disorders (e.g., Mucopolysaccharidosis, Gaucher Disease)
    • Peroxisomal Disorders (e.g., Zellweger Spectrum Disorders)
    • Metabolic Disorders (e.g., Propionic Acidemia, Methylmalonic Acidemia)
    • Neurodegenerative Diseases (e.g., Parkinson’s Disease, Alzheimer’s Disease, Huntington’s Disease
• Syndromes with Mitochondrial DNA Variants of Uncertain Significance
  Some mtDNA mutations are detected but not yet fully understood in how they cause disease.