Mitochondrial disorders

Abstract

Primary mitochondrial disorders are a group of clinically variable and heterogeneous inborn errors of metabolism (IEMs), resulting from defects in cellular energy, and can affect every organ system of the body. Clinical presentations vary and may include symptoms of fatigue, skeletal muscle weakness, exercise intolerance, short stature, failure to thrive, blindness, ptosis and ophthalmoplegia, nystagmus, hearing loss, hypoglycemia, diabetes mellitus, learning difficulties, intellectual disability, seizures, stroke-like episodes, spasticity, dystonia, hypotonia, pain, neuropsychiatric symptoms, gastrointestinal reflux, dysmotility, gastrointestinal pseudo-obstruction, cardiomyopathy, cardiac conduction defects, and other endocrine, renal, cardiac, and liver problems. Most phenotypic manifestations are multi-systemic, with presentations varying at different age of onset and may show great variability within members of the same family; making these truly complex IEMs. Most primary mitochondrial diseases are autosomal recessive (AR); but maternally-inherited [from mitochondrial (mt) DNA], autosomal dominant and X-linked inheritance are also known. Mitochondria are unique energy-generating cellular organelles, geared for survival and contain their own unique genetic coding material, a circular piece of mtDNA about 16,000 base pairs in size. Additional nuclear (n)DNA encoded genes maintain mitochondrial biogenesis by supervising mtDNA replication, repair and synthesis, which is modified during increased energy demands or physiological stress. Despite our growing knowledge of the hundreds of genetic etiologies for this group of disorders, diagnosis can also remain elusive due to unique aspects of mitochondrial genetics. Though cure and FDA-approved therapies currently elude these IEMs, and current suggested therapies which include nutritional supplements and vitamins are of questionable efficacy; multi-center, international clinical trials are in progress for primary mitochondrial disorders.

Keywords: Mitochondria; energy metabolism; heteroplasmy; mtDNA; nDNA.

Figure 1

Overview of OXPHOS and complex I–V function and genetic characteristics. Green lines represent mitochondrial inner membrane and mitochondrial outer membrane. Complexes are color coded and noted in white roman numerical; I—red, II—pink, III—yellow, IV—green and V—turquoise. Genes known with human disease are noted in black caps. Also noted is coenzyme Q (CoQ) with complex II and cytochrome c in between complex II& III. Arrows denote electron transport. Total known number of DNA subunits is noted below.

Figure 2

Overview of mitochondrial depletion disorders. Green lines represent mitochondrial inner membrane and mitochondrial outer membrane. Associated enzymes and proteins are noted in italics and red star represent correlating nucDNA disorders.

Figure 3

Overview of other disorders involving mitochondria. Green lines represent mitochondrial inner membrane and mitochondrial outer membrane. Enzyme names are written in italics and mitochondrial enzyme deficiencies are shown in the red star shapes. *, reaction occurs in mitochondrial intermembrane space; **, reaction occurs on mitochondrial outer membrane; ***, reaction occurs on mitochondrial inner membrane. PDHAD, pyruvate dehydrogenase E1-alpha deficiency; PDHDD, pyruvate dehydrogenase E2 deficiency; DLDD, dihydrolipoamide dehydrogenase deficiency; OPA9, optic atrophy-9; ICRD, infantile cerebellar-retinal degeneration; D2HGA2, D-2-hydroglutaric aciduria 2; FMRD, fumarase deficiency; EIEE, early infantile epileptic encephalopathy; MSUD, maple syrup urine disease; IBDD, isobutyryl-CoA dehydrogenase deficiency; HIBCHD, β-hydroxybutyryl-CoA dehydrogenase deficiency; MMSDHD, methylmalonate semialdehyde dehydrogenase deficiency; MCCD, β-methylcrotonyl-CoA carboxylase deficiency; MGCA, β-methylglutaconic aciduria; HMGCLD, HMG-CoA lyase deficiency; CPS I, carbamoyl phosphate synthetase I deficiency; OTC, ornithine transcarbamoylase deficiency.