RT Book, Section
A1 DiMauro, Salvatore
A1 Debray, François-Guillaume
A1 Hirano, Michio
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181438163
T1 Clinical Diagnostic and Therapeutic Approach to the Patient with Suspected Mitochondrial Disease
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=1181438163
RD 2024/04/20
AB This  chapter  focuses  on  the  clinical  approach  to  diseases  with  impaired  respiratory  chain  function.  Diseases  of  other  mitochondrial  pathways,  such  as  disorders  of  fatty  acid  oxidation  (FAO),  the  Krebs  cycle,  the  urea  cycle,  and  pyruvate  oxidation  are  addressed  in  other  chapters.Respiratory  chain  diseases  are  clinically  very  heterogeneous.  They  include  multisystem  or  monosystem  disorders,  and  can  have  congenital,  infantile,  or  late-onset  presentations.  They  may  be  familial  or  sporadic.  Familial  cases  may  result  from  mutations  of  nuclear  DNA  (nDNA),  which  show  Mendelian  transmission,  or  of  mitochondrial  DNA  (mtDNA),  which  show  maternal  transmission.  Mitochondrial  diseases  are  frequently  but  not  invariably  associated  with  characteristic  laboratory  abnormalities  (e.g.,  elevated  blood  or  CSF  lactate,  characteristic  findings  on  muscle  biopsy  and  brain  MRI,  and  known  pathogenic  genetic  changes).Syndromology.  Certain  signs  or  combinations  of  signs  should  alert  clinicians  to  a  possible  mitochondrial  disorder.  Many  are  due  either  to  mtDNA  mutations  or  to  nuclear  mutations  affecting  mtDNA  maintenance.  Progressive  external  ophthalmoplegia  (PEO)  is  often  a  telltale  sign  of  mitochondrial  dysfunction,  present  in  isolation  or  associated  with  multiple  symptoms,  manifesting  as  a  “PEO-plus”  syndrome  often  with  involvement  of  extramuscular  systems  excluding  the  CNS,  or  as  “mitochondrial  encephalomyopathy”  such  as  in  Kearns–Sayre  syndrome  (KSS).  Two  mitochondrial  syndromes  frequently  cause  optic  atrophy:  autosomal  dominant  optic  atrophy  (DOA)  and  Leber  hereditary  optic  neuropathy  (LHON).  The  former  is  due  to  mutations  in  the  gene  (OPA1)  encoding  a  crucial  dynamin-like  mitochondrial  fusion  protein;  the  latter  is  predominantly  due  to  mutations  in  three  mtDNA  genes  encoding  complex  I  subunits  (ND1,  ND4,  and  ND6).  Stroke-like  episodes  with  mitochondrial  encephalomyopathy  and  lactic  acidosis  suggest  MELAS  syndrome,  which  appears  most  commonly  in  older  children  or  adults  and  can  result  from  a  variety  of  mtDNA  mutations.  A  common  infantile  mitochondrial  disorder  is  hepatocerebral  syndrome  (Alpers–Huttenlocher  syndrome),  a  devastating  condition  with  liver  failure  and  intractable  seizures,  due  to  POLG  mutations  causing  mtDNA  depletion.  The  absence  of  a  classical  mitochondrial  syndrome  does  not  exclude  a  mitochondrial  disease,  and  many  mitochondrial  disease  patients  present  with  a  single  complaint.Molecular  prenatal  diagnosis  is  straightforward  for  nuclear  encoded  conditions  if  the  causal  mutations  are  known.  For  diseases  caused  by  mtDNA  mutations,  some  degree  of  prenatal  prediction  of  clinical  outcome  is  possible  for  certain  mutations  in  protein-coding  mtDNA  genes.  An  example  is  m.8993T>G,  which  causes  neuropathy,  ataxia,  and  retinitis  pigmentosa  (NARP),  and  maternally  inherited  Leigh  syndrome  (MILS).  For  NARP/MILS,  a  mutation  level  below  30%  in  chorionic  villus  samples  (CVS)  or  in  amniocytes  suggests  a  favorable  outcome,  but  a  mutant  fraction  exceeding  70%  is  an  ominous  sign,  and  intermediate  mutation  loads  leave  us  uncertain  about  the  outcome.  Prenatal  diagnosis  is  considerably  less  reliable  for  mutations  in  mtDNA  genes  of  protein  synthesis,  such  as  tRNA  genes  (e.g.,  the  MELAS  m.3243A>G  mutation),  because  the  mutation  load  in  prenatal  samples  may  differ  considerably  from  that  of  fetal  tissues  and  the  mutant  fraction  can  shift  during  gestation  and  after  birth.There  are  three  major  therapeutic  strategies  for  mitochondrial  diseases.  They  focus  on  root  causes,  on  downstream  mechanisms,  and  on  clinical  endpoints.  Therapies  directed  toward  root  causes  include  the  following.  (a)  Mitochondrial  replacement  therapy  (MRT):  MRT  ...