Health

Article of the week: Beyond the mitochondria, Leber’s Hereditary Optic Neuropathy pg. 2Symptoms pg. 3 Causes pg. 4-6Diagnosis pg. 7Research pg. 8Living with LHON pg. 8-11

Leber’s Hereditary Optic Neuropathy

Beyond the mitochondria...

  One  of  thousands  of  young  mitochondrial  diseases,  Leber’s  Hereditary  Optic  Neuropathy,  LHON,  is  a  devastating  hereditary  disease  that  has  not  reached  global  awareness. Characterized  by  sudden  vision  loss,  there  is  no  cure  for  LHON  and  no  concrete  medical  treatments.  Yet,  the  global  LHON  community  strives  to  always  stay  positive.  

What  is  LHON?  LHON  is  an  inherited  form  of  vision  loss.  The  disease  is  not  progressive;  it  is  a  sudden  and  painless  loss  of  sight.  Speci>ically,  the  onset  of  LHON  is  characterized  by  a  sudden  blurring  of  central  vision  in  one  eye  (“LHON  101”).  In  two  to  three  months  later  the  other  eye  looses  its  central  vision  as  well.  This  is  the  classic  pattern  of  LHON.  However,  in  25%  of  cases  loss  of  vision  is  bilateral  at  onset  (Chinnery).  Over  time,  visual  acuity  in  both  eyes  decreases  along  with  colour  vision.  

The  cloudiness  that  LHON  patients  experience  mainly  affects  the  central  vision  of  the  eyes.  Therefore,  they  are  able  to  use  their  peripheral  vision  to  move  around  and  perform  their  daily  tasks.  However,  tasks  that  require  central  vision,  such  as  reading,  driving  and  recognizing  faces,  are  nearly  impossible  (“LHON  101”).  Sometimes  central  vision  will  increase  in  a  small  amount  of  cases,  but  it  is  rare.  In  most  cases  of  LHON,  vision  loss  is  profound  and  permanent.  Most  people  who  have  the  disease  qualify  for  registration  as  legally  blind  (visual  acuity  <20/200)  (Chinnery).              

Article of the week!

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SymptomsVision  loss  it  typically  the  only  symptom  of  LHON  (“Leber’s”).  

However,  some  patients  experience  additional  symptoms  including...• Movement  disorders• Tremors• Cardiac  conduction  effects  (abnormalities  of  electrical  signals  that  control  the  heartbeat)

• Multiple  Sclerosis-­‐like  symptoms  including  muscle  weakness,  poor  coordination  and  numbness  

IncidenceThe  incidence  of  LHON  is  unknown  in  most  populations  as  it  it  very  rare.  However,  some  incidence  rates  do  exist  and  are  shown  in  the  diagram  below  (“LHON  101”)  (“Leber’s”).  

100  Americans  loose  central  vision  to  LHON  every  year.  

LHON affects 1 in every 30 000 to 50 000 people in northeast England and

Finland.

Quick  Fact:  As  mitochondrial  disease  research  continues,  researchers  are  >inding  that  more  illness  are  linked  to  mitochondrial  defects.  Exempli>ied  through  the  symptoms  of  LHON,  it  is  possible  that  Multiple  Sclerosis  falls  under  the  umbrella  of  mitochondrial  disease.    

It is estimated that 35 000 people have LHON worldwide.

Who  does  LHON  affect?  People  who  have  LHON  have  a  mutation  in  their  mitochondrial  DNA,  which  will  be  discussed  further  in  this  article.  LHON  usually  triggers  in  a  person’s  teens  or  twenties  (“Leber’s”).  However,  one  is  never  “too  old”  or  “too  young”  to  be  affected.  Rare  cases  have  been  reported  in  early  childhood  and  late  adulthood.    For  unknown  reasons,  LHON  also  seems  to  affect  males  much  more  than  females.  In  fact,  males  are  5-­‐4  times  more  likely  to  experience  the  disease  (Chinnery).  

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Cause:  InheritanceAs  previously  mentioned,  LHON  is  a  hereditary  disease.  This  means  that  it  is  passed  down  from  parent  to  child.  However,  LHON  falls  under  a  special  category  of  hereditary  disease.  It  is  a  mitochondrial  disease.  When  an  embryo  is  formed,  only  the  egg  cell  from  the  mother  provides  mitochondria  to  the  growing  fetus.  Therefore,  if  the  mother  has  mutated  mitochondria,  her  child  will  automatically  inherit  them.  Fathers  will  never  pass  mitochondria  to  the  embryo  by  their  sperm.  Furthermore,  mothers  may  provide  the  fetus  with  varying  degrees  of  mitochondrial  mutations  depending  on  the  amount  of  mutated  mitochondria  in  their  egg.

 Although  the  mutated  gene  runs  through  the  family,  most  people  have  no  family  history  of  the  mitochondrial  disorder  (“LHON  101”).  This  is  because  not  all  people  who  carry  the  mutated  gene  that  leads  to  LHON  experience  the  disease.  In  fact,  more  than  50%  of  males  and  85%  of  females  that  carry  the  mutation  do  not  develop  LHON  symptoms  (Chinnery).  The  trigger  of  the  disease  remains  unknown  at  this  time.  However,  researchers  believe  environmental  factors  including  alcohol  and  tobacco  use  may  be  involved.        

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Gene MT-ND1 MT-ND4 MT-ND4L MT-ND6

Protein made by gene

NADH Dehydrogenase 1

NADH Dehydrogenase 4

NADH Dehydrogenase 4L

NADH Dehydrogenase 6

Most common mutation

m. 3460G>A m. 11778G>A m. 10663T>C m. 14484T>C

Incidence (%)

13% of LHON cases

70% of LHON cases

Very rare mutation

14% of LHON cases and most common mutation among the French Canadian population

Cause of mutation

The mutation replaces the nucleotide Guanine with Adenine at the mtDNA position 3460

The mutation replaces the amino acid arginine with the amino acid histidine at the protein position 340

The mutation replaces the amino acid valine with the amino acid alanine at the protein position 65

The mutation replaces the amino acid methionine with the amino acid valine at the protein position 64

90%  of  individuals  with  LHON  have  one  of  the  three  mutations,  3460,  11778  or  14484. (Chinnery)

LHON  is  caused  by  mutations  of  four  different  genes  shown  in  the  table  below  (“Leber’s”).  Researchers  estimate  there  are  approximately  40  mutations  in  total  (“Leber’s”).

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Cause:  Sight  DeteriorationThe  loss  of  central  vision  in  LHON  cases  is  caused  by  the  atrophy  of  the  optic  discs  of  the  eyes  through  the  deterioration  and  death  of  cells.  LHON  patients  also  have  enlarged  central  or  centrocecal  scotoma  that  adds  to  the  loss  of  vision.  The  optic  discs  are  considered  the  head  of  the  optic  nerve,  a  channel  that  transports  information  from  the  retina  to  the  brain.  Therefore,  the  deterioration  causes  the  severe  loss  of  central  vision  experienced  by  LHON  patients.    It  remains  unclear  how  the  genetic  mutations  directly  cause  the  death  of  cells  in  the  optic  nerve.    

Cause:  Metabolic  ProcessAll  mitochondrial  mutations  involved  with  LHON  affect  the  Complex  I  proteins  in  the  Electron  Transport  Chain  (ETC)  of  the  mitochondria.  The  ETC  is  a  protein  chain  located  in  the  inner  mitochondrial  membrane.  It  is  responsible  for  fusing  inorganic  phosphate  molecules  (Pi)  to  adenosine  diphosphate  (ADP)  to  make  adenosine  triphosphate  (ATP),  the  molecule  that  provides  energy  to  every  cell  in  the  human  body.  Protein  Complex  I  is  the  >irst  protein  in  the  ETC.  It  speci>ically  transports  H+  ions  from  the  co-­‐enzyme  NADH  and  transports  the  most  H+  molecules  out  of  the  other  proteins  in  the  ETC.  

Every  LHON  mutation  codes  for  an  improper  protein  in  the  >irst  protein  complex  (“Leber’s”).  As  a  result,  Complex  I  cannot  accept  H+  from  NADH  co-­‐enzymes.  As  Complex  I  is  the  >irst  protein  in  the  ETC  very  few  H+  atoms  are  actively  transported  to  the  inter  mitochondrial  space.  Thus,  a  improper  chemical  concentration  gradient  is  formed  and  ATP  Synthase  does  not  facilitate  enough  H+  atoms  back  into  the  mitochondrial  matrix.  Therefore,  little  ATP  is  created.  

People  with  LHON  depend  on  the  4  ATP  produced  by  substrate-­‐level  phosphorylation  produced  in  glycolysis  and  the  Kreb’s  Cycle.    They  also  depend  on  the  4  ATP  created  by  FADH2  per  glucose  molecule,  another  co-­‐enzyme  that  is  transported  through  Protein  Complex  VI.  Finally,  some  ATP  is  created  from  NADH  through  Protein  Complex  V,  but  very  little.    

Normal  eye   LHON  eye

Figure  1.  Normal  Electron  Transport  Chain.  The  protein  complexes  actively  transport  H+  ions  from  the  NADH  co-­‐enzymes  into  the  inter  mitochondrial  space,  creating  a  chemical  concentration  gradient.  The  facilitation  of  H+  ions  back  into  the  mitochondrial  matrix  by  ATP  Synthase  fused  ADP  and  Pi  

Inter  mitochondrial  space

Mitochondrial  Matrix

Protein  Complex  I

Figure  2.  In  LHON,  Protein  Complex  I  is  un  able  to  accept  H+  ions  from  NADH.  Therefore,  less  H+  builds  up  in  the  inter  mitochondrial  space  and  less  energy  is  created.  

Protein  Complex  I Inter  mitochondrial  space

NADH NADH

Very little ATP produced

NADH NADH NADH

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DiagnosisIf  you  are  aware  that  your  maternal  bloodline  carries  the  LHON  gene  and  you  suddenly  experience  profound  vision  loss  it  is  extremely  likely  that  you  have  developed  the  LHON  disease  (“LHON  101”).  However,  if  there  is  no  family  history  searching  for  diagnosis  can  be  quite  time  consuming  and  frustrating.  As  LHON  is  so  rare  it  is  commonly  mistaken  for  other  common  eye  conditions  or  brain  tumors  at  its  time  of  onset  (“LHON  101”).  Most  people  believe  they  just  need  glasses.  

However,  static  and  kinetic  >ield  testing  at  an  optometrist  can  help  push  the  diagnosis  of  LHON  (Chinnery).  Optometrists  can  study  the  eyes  of  the  patient  to  determine  if  their  optic  discs  are  atrophic  and  if  they  have  an  enlarged  scotoma.    

Presently,  a  simple  blood  test  can  determine  whether  a  person  carries  one  of  the  three  primary  LHON  mutations.  Other  more  complicated  blood  tests  can  analyze  a  person’s  entire  mitochondria  (“Leber”).        If  the  LHON  gene  is  known  to  run  in  the  maternal  bloodline  of  a  family,  prenatal  testing  is  available  to  determine  the  likelihood  of  the  unborn  child  developing  the  disease  (Chinnery).  

TreatmentUnfortunately,  there  are  no  concrete  medical  treatments  for  LHON,  nor  is  there  a  cure  (“LHON  101”).  Management  of  patients  is  largely  supportive.  Visual  aids  are  used,  including  high-­‐magni>ication  glasses  and  assistive  technology.  Also,  occupational  rehabilitation  and  registration  with  relevant  social  services,  such  as  psychiatric  counselling  unemployment  services,  and  are  utilized.    

Therapy  Under  Investigation:  Idebenone  Clinical  trials  of  oral  administration  of  Idebenone  has  proved  to  help  those  who  are  in  the  early  stages  of  the  LHON  disease  (Chinnery).  Idebenone  is  a  synthetic  form  of  co-­‐enzyme  Q10.  Naturally,  this  co-­‐enzyme  aids  the  Electron  Transport  Chain  produce  ATP.  The  supplement  of  Q10  may  help  the  mitochondria  of  patients  build  up  their  proper  H+  gradients  to  create  ATP.  

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ResearchLHON  is  an  extremely  rare  disease.  As  a  result,  most  vision  professionals  do  not  study  it  (“LHON  101”).  Some  may  spend  their  entire  professional  career  without  hearing  about  LHON.  However,  some  research  is  being  conducted  at  present.

John  Guy,  M.D.,  an  opthalmology  professor  at  the  Bascom  Palmer  Eye  Institute  in  Miami,  Florida  has  been  conducting  cutting-­‐edge  research  on  LHON.  His  studies  focus  of  gene  therapy  for  the  11778  mutation.  Dr.  Guy  has  successfully  used  protein  carriers  to  introduce  healthy  genes  in  mitochondria  using  experimental  models.  He  is  now  studying  whether  replacing  the  mutated  genes  will  stop  the  deterioration  of  the  cells  on  the  optic  nerve.  In  2009,  he  received  a  $4.7  million  grant  from  the  National  Eye  Institute  to  continue  his  research.  (“Bascom”)                          

The  International  Foundation  for  Optic  Nerve  Disease  has  spent  incredible  time  and  efforts  to  study  the  largest  LHON  pedigree  in  the  world.  The  foundation  has  made  12  rural  trips  to  Brazil  to  document  the  path  of  the  LHON  disease  (“Leber”).  Nearly  95%  of  the  300  member  pedigree  with  the  LHON  11778  mutation  was  studied.      Scientists  involved  in  this  projects  including  Dr.  Alfredo  A.  Sadun  and  Dr.  Valerio  Carelli  have  made  speeches  around  the  world  about  their  work  (“Leber”).  

Living  with  LHON

The  onset  of  LHON  can  be  devastating.  One  goes  from  being  perfectly  normal  to  being  in  the  range  of  legally  blind  in  a  matter  of  months.  Many  people  feel  that  their  life  is  being  taken  away  (“LHON  101”).  Not  being  able  to  do  simple  things  like  reading,  driving,  and  recognizing  faces  impedes  a  person’s  independence.  Although  LHON  patients  are  faced  with  an  completely  new  life  very  suddenly,  it  is  important  to  stay  positive.  It  is  possible  to  live  a  full,  long  life  with  LHON.  With  time,  people  can  continue  to  do  what  they  love.  Luck,  there  are  many  resources  that  help  the  blind  and  vision  impaired.  

“I am determined to live my life as normally as possible.” - Jeremy Poincenot, LHON mutation 11778; international speaker and world blind golf champion

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Counselling

Speaking  with  a  counsellor  can  be  helpful  in  talking  through  the  grief,  fear  and  anxiety  brought  upon  by  the  loss  of  vision  (“LHON  Community”).  Another  emotional  stress  patients  may  face  is  the  hope  of  rare  spontaneous  recovery.  Counselling  may  help  sort  out  these  con>licting  emotions  and  provide  coping  strategies  to  the  patient.    Community  counsellings  centres,  such  as  the  Family  Counselling  Centre  of  Brant,  counselling  services  through  hospitals  and  private  practices  are  available  to  LHON  patients.    The  costs  of  counselling  are  listed  in  the  “LHON  Costs”  table.      

Assistive  Technology

With  the  boom  of  modern  technology,  there  are  many  devices  out  there  to  help  people  with  LHON.  Magnifying  equipment  such  as  CCTVs  and  portable  electronic  magni>iers  can  help  LHON  patients  read  with  their  peripheral  vision  (“LHON  Community”).  E-­‐books,  offered  through  most  public  library  systems,  can  also  be  useful  for  magnifying  text.    With  voice  commands  and  audio  play  back,  audio  books,  talking  cell  phones  and  Apple  products  can  aid  LHON  patients  as  they  have  voice  command  and  magni>ication  functions.  Finally  computer  screen  reading  software  can  magnify  test  for  the  visually  impaired  (“LHON  Community”).  The  costs  of  these  products  

Education

Many  people  >irst  experience  LHON  when  then  are  in  high  school  or  post-­‐secondary  education.  For  those  in  high  school,  there  is  typically  a  vision  specialist  associated  with  the  school  or  school  board  who  can  help  with  the  visually  impaired  student’s  transition.  In  colleges  and  universities,  there  is  usually  a  Student  Disability  Centre  that  will  notify  professors  and  help  the  student  with  their  school  work  (“LHON  Community”).  Most  schools,  both  secondary  and  post-­‐secondary,  provide  access  to  assistive  technology  like  CCTVs.  

In  Brantford,  visually-­‐impaired  students  who  are  in  grades  1-­‐12  have  the  ability  to  attend  a  famous  school,  W.  Ross  Macdonald  School.  This  school  provides  visually-­‐impaired  students  and  blind  students  with  the  skills  they  will  need  to  live  an  independent  life.  Not  only  do  students  follow  standard  curriculum  but  they  also  have  opportunities  to    do  CO-­‐OP  programs  in  the  community.      

Employment

Depending  on  a  person’s  career,  those  who  have  LHON  may  need  to  >ind  alternative  jobs  because  of  their  impaired  vision.  The  Canadian  Disability  Vocational  Rehabilitation  Program  can  help  LHON  patients  by  providing  employment  counselling,  improving  workplace  skills,  planning  their  return  to  work,  and  developing  job  search  skills  (“Vocational”).              

“I often wondered how I was going to do any type of purposeful work that I enjoyed. Technology advanced quickly in the 1990’s and 2000’s. It has opened a world of accessibility. I recently went back to school and obtained a joint law degree and masters of business administration.”- Locke; LHON mutation 3460

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Treatment/Service Cost ($)

Optometrist 18 and under: visits are covered by OHIPOptometrist

18 and older: approximately $120/ appointment

Counselling Community counselling services: FreeCounselling

Hospital counselling services: Free and a referral by a doctor is usually required

Counselling

Private counselling services: $50- $240 / hour

Assistive Technology CCTV and ALADIN screen magnifiers: up to $3 000Assistive Technology

Apple products (iPad): $259- $800

Assistive Technology

E-books: Free through public library systems or $15- $25 each at book stores.

Assistive Technology

Portable Electronic Magnifier: up to $600

Assistive Technology

Computer Software (ZoomText, JAWS, Kurzweil): up to $400

Idebenone up to $89 for 150 capsules if not covered by an insurance plan

ArgentinaFacebook Group: https://www.facebook.com/groups/586585178062529/

CanadaFacebook Group: https://www.facebook.com/groups/577647358984474/

FinlandFinnish Federation of the Visually Impaired: http://www.nkl.fi/7

LHON OutreachConnecting with other LHON families around the world can be very rewarding for those struggling with the disease. Register to be connected with other LHON families by going to http://www.lhon.org/lhon/Register.html. As well, here are the websites of support groups and facebook pages for LHON in several countries (“LHON Community”).

LHON  Costs  Table

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FranceOuvrir les Yeux: http://www.ouvrirlesyeux.org

GermanyFacebook Group: https://www.facebook.com/groups/414613055222957

ItalyFacebook Group: https://www.facebook.com/groups/ChiaraBerni/

NetherlandsFacebook Group: https://www.facebook.com/groups/615379848498198/

SpainASANOL: http://www.asanol.com

SwedenLHON Eye Society and Facebook Group: http://www.lhon.se

InternationalFacebook Group: https://www.facebook.com/groups/29805437752

Continuing  ResearchI  believe  that  LHON  research  should  continue  to  pursue  a  cure.  LHON  is  a  devastating  disease  that  affects  a  variety  of  people  around  the  world.  I  believe  advanced  research  will  bring  upon  important  discoveries  that  will  help  the  30  000  people  living  with  LHON  and  will  shed  light  on  other  areas  of  mitochondrial  diseases.  A  cure  is  reachable  and  we  need  to  reach  it  together.  

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Work  Cited  

“Bascom  Palmer  Eye  Institute  Researcher  Receives  NEI  Grant  for  Gene  Therapy  Trial.”  (May  

4,  2009).  University  of  Miami  School  of  Medicine.  Retrieved,  Nov.  9,  2014,  from  

http://www.med.miami.edu/news/view.asp?id=1098

Chinnery,  Patrick  and  Yu-­‐Wai-­‐Man,  Patrick.  “Leber  Hereditary  Optic  Neuropathy.”  

GeneReviews®.  Retrieved  Nov.  7,  2014,  from  http://www.ncbi.nlm.nih.gov

/books/NBK1174/

 “Leber  Hereditary  Optic  Neuropathy.”  (29  Sep.  2013).    International  Foundation  for  Optic  

Nerve  Disease.  Retrieved,  Nov  9.  2014,  from  http://www.ifond.org

/lhon.php3

“Leber’s  hereditary  optic  neuropathy.”  (Dec.  2013).  Genetics  Home  Reference.  Retrieved  

Nov.  7,  2014,  from  http://ghr.nlm.nih.gov/condition/leber-­‐hereditary-­‐optic-­‐

neuropathy

“LHON  Community.”  LHON.  Retrieved  Nov.  8,  2014,  from  http://www.lhon.org

/lhon/LHON_community.html

“LHON  101.”  LHON.  Retrieved  Nov.  7,  2014,  from  http://www.lhon.org

/lhon/LHON_101.html

“Vocational  Rehabilitation  Program.”  (July  30,  2013).  Service  Canada.  Retrieved  Nov.  9,  

2014,  from  http://www.servicecanada.gc.ca/eng/services/pensions/cpp

/disability/voc-­‐rehab.shtml

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