RT Book, Section
A1 Lombès, Anne
A1 Thorburn, David R.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181440247
T1 Laboratory Diagnosis of Mitochondrial Diseases
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181440247
RD 2024/04/25
AB The  definition  of  mitochondrial  diseases  used  in  this  chapter  defines  these  diseases  as  conditions  in  which  a  defect  of  the  mitochondrial  oxidative  phosphorylation  (OXPHOS)  pathway  is  a  key  contributor  to  the  pathophysiology  of  the  disease.  Classifying  which  genes  fall  under  that  definition  remains  debatable  for  some  genes  where  the  pathophysiology  is  not  yet  completely  understood.The  mitochondrial  OXPHOS  pathway  consists  of  five  heteropolymeric  enzyme  complexes  in  the  mitochondrial  inner  membrane,  containing  more  than  80  different  proteins,  plus  the  two  electron  carriers  ubiquinone  and  cytochrome  c.  OXPHOS  complexes  can  be  further  assembled  into  supercomplexes.  A  functional  OXPHOS  pathway  relies  on  the  interaction  of  two  genomes.  The  mitochondrial  DNA  (mtDNA)  encodes  13  of  the  OXPHOS  proteins  plus  2  rRNAs  and  22  tRNAs  required  for  translation  of  the  mtDNA  genome.  The  nuclear  genome  encodes  hundreds  of  proteins  essential  for  OXPHOS  function.  These  include  subunits  and  assembly  factors  for  each  complex  plus  all  the  machinery  required  for  import,  processing  and  quality  control  of  mitochondrial  proteins,  replication  and  expression  of  mtDNA  as  well  as  synthesis  of  redox  centers,  electron  carriers,  cofactors,  nucleotides  and  maintaining  an  appropriate  membrane  milieu  for  stability  of  the  OXPHOS  complexes.  Given  this  genetic  complexity,  it  is  not  surprising  that  mitochondrial  diseases  are  now  known  to  comprise  at  least  200  monogenic  diseases.Mitochondrial  diseases  encompass  a  very  large  number  of  conditions  with  a  huge  clinical  spectrum,  with  signs  affecting  any  tissue  in  the  body,  with  onset  at  any  age,  and  with  any  type  of  inheritance.  The  functional,  structural  and  genetic  complexity  of  OXPHOS  directly  explains  the  wide  diversity  of  mitochondrial  diseases.  In  most  cell  types,  in  particular  neuronal  and  muscle  cells,  OXPHOS  is  producing  more  than  90%  of  the  cellular  ATP.  In  parallel  it  has  central  roles  in  the  maintenance  of  the  cellular  redox  potential,  inner  membrane  potential  and  reactive  oxygen  species  metabolism.Many  mitochondrial  diseases  are  multisystemic,  involving  several  tissues  unrelated  by  functional  or  embryological  link.  However  tissue-specificity  is  also  frequent  and  the  pathophysiological  mechanisms  remain  largely  hypothetical.  In  mitochondrial  diseases  affecting  a  single  tissue,  demonstration  of  the  mitochondrial  defect  can  be  difficult  because  most  histological  and  enzymatic  analyses  are  made  in  muscle,  which  may  be  spared  by  the  disease.  In  addition  a  mitochondrial  defect,  even  severe  but  affecting  a  tissue  with  minor  mass,  will  have  little  influence  on  the  global  metabolic  status  that  is  analysed  in  blood  and  urine  samples.The  initial  steps  in  investigating  possible  mitochondrial  disease  involve  assessment  of  family  history  and  clinical  features,  with  a  focus  on  recognizing  classical  mitochondrial  syndromes  and  multisystem  disease,  together  with  consideration  of  possible  alternative  diagnoses.  In  most  cases,  the  next  steps  involve  non-invasive  studies  on  body  fluids  to  detect  any  alteration  in  cellular  redox  ratio  or  accumulation  of  substrates  upstream  of  the  deficient  metabolic  step,  such  as  lactate,  pyruvate  or  intermediates  of  the  Krebs  cycle.  Together  with  imaging,  these  investigations  can  guide  whether  specific  single  gene  tests,  gene  panels  or  whole  exome  sequencing  should  be  performed  or  if  the  patient  should  proceed  to  tissue  biopsies.Traditionally,  most  patients  with  suspected  mitochondrial  disease  have  been  investigated  by  performing  a  ...