Chapter 30: Mitochondrial Disorders

Substrate transport

Carnitine palmitoyltransferase (CPT)

Primary systemic/muscle carnitine deficiency

Secondary carnitine deficiency

Combined carnitine and CPT deficiency

Substrate utilization

Pyruvate decarboxylase deficiency

Pyruvate dehydrogenase deficiency

Pyruvate carboxylase deficiency

Fatty acid β-oxidation defects

Kreb cycle

Fumarase

α-Ketoglutarate dehydrogenase deficiency

Dihydrolipoyl dehydrogenase

Oxidation/phosphorylation coupling

Luft syndrome: Loose coupling with hypermetabolism

Respiratory chain

Complex I

Complex II

Complex III

Complex IV

Complex V

Combinations of I–V

1. Mitochondrial DNA mutations

   1. Large-scale deletions

      1. Kearns–Sayre syndrome

      2. PEO

   2. Mutations in mtDNA protein–coding genes

      1. ATP6 is associated with Leigh syndrome and NARP

      2. Cytochrome b is associated with exercise intolerance and recurrent myoglobinuria

      3. Cytochrome c oxidase is associated with fatal and benign infantile myopathies, Leigh syndrome, MELAS, recurrent rhabdomyolysis

   3. Mutations in mitochondrial tRNA and rRNA genes

      1. MERRF is usually associated with mutations in tRNALys gene. MERRF has also been associated with mutations in tRNALeu and tRNASer

      2. MELAS is usually associated with mutations in tRNALeu gene. MELAS also occurs with mutations in tRNAVal, tRNACys, ND5 of complex 1, and in cytochrome b

2. Nuclear gene mutations

   1. Nuclear mutations associated with mtDNA maintenance and replication (multiple mtDNA deletions and mtDNA depletion)

      1. Thymidine phosphorylase gene (TYMP) is associated with autosomal recessive MNGIE

      2. Adenine nucleotide translocator 1 (ANT1) is associated with autosomal dominant PEO

      3. Twinkle (C10orf2) is associated with autosomal dominant PEO and SANDO

      4. Polymerase gamma (POLG1 and POLG2) is associated with autosomal recessive and dominant PEO, SANDO, MIRAS

      5. Ribonucleotidase reductase (RRM2B) is associated with MNGIE and PEO

      6. Thymidine kinase 2 (TK2) is associated with severe myopathy

      7. DNA replication helicase/nuclease 2 (DNA2) is associated with PEO

      8. Deoxyguanosine kinase (DGUOK) is associated with PEO, recurrent rhabdomyolysis, and mtDNA depletion myopathy

      9. Paraplegin (SGP7) is usually associated with hereditary spastic paraplegia but can be associated with PEO and spasticity

   2. Nuclear mutations associated with abnormal mitochondrial fusion/fission

      1. Mitofusin 2 (MFN2) associated with CMT2A

      2. Ganglioside-induced differentiation associated-protein 1 (GDAP1) associated with CMT2K and CMT4A

      3. Optic atrophy 1 (OPA1) associated with optic atrophy 1 syndrome/CMT with optic atrophy

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