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Chapter 30: Mitochondrial Disorders

INTRODUCTION

Mitochondrial myopathies and neuropathies or neuromyopathies refer to a heterogeneous group of disorders caused by dysfunction of mitochondria.1–10 Mitochondrial disorders can be classified according to the associated biochemical, genetic defects, or clinical phenotype (Tables 30-1,30-2,30-3). One difficulty in classifying patients by any particular scheme is the clinical-phenotypic heterogeneity associated with specific mitochondrial mutations and the genetic heterogeneity in well-defined clinical phenotypes that are seen with mitochondrial disorders.

TABLE 30-1.CLASSIFICATION OF THE MITOCHONDRIAL MYOPATHIES BY METABOLIC FUNCTION AFFECTED
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TABLE 30-1.CLASSIFICATION OF THE MITOCHONDRIAL MYOPATHIES BY METABOLIC FUNCTION AFFECTED
Metabolic Function Defects
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’s syndrome: Loose coupling with hypermetabolism
Respiratory chain Complex I
Complex II
Complex III
Complex IV
Complex V
Combinations of I–V

Reproduced with permission from Walsh RJ. Metabolic Myopathies. Continuum. 2006;12(3):76–120.

TABLE 30-2.CLASSIFICATION OF MITOCHONDRIAL DISORDERS BY GENETIC MUTATIONS
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TABLE 30-2.CLASSIFICATION OF MITOCHONDRIAL DISORDERS BY GENETIC MUTATIONS

  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 paraglegia 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 ...

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