Leber's hereditary optic neuropathy pdf

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

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Article of the week!

Beyond the mitochondria...

Leber’s Hereditary Optic Neuropathy

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?

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).

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.

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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.

Symptoms Vision 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

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).

Incidence The 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”).

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

100 Americans loose central vision to LHON every year.

It is estimated that 35 000 people have LHON worldwide.

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Cause: Inheritance As 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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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”).

Gene

MT-ND1

MT-ND4

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 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

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

MT-ND4L

MT-ND6

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

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Cause: Metabolic Process All 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.

Protein Complex I

Inter mitochondrial space

Mitochondrial Matrix

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

Protein Complex I

NADH

NADH

NADH

NADH

Inter mitochondrial space

NADH

Very little ATP produced

People with LHON depend on the 4 ATP 2. In LHON, Protein Complex I is un able to accept H+ ions from produced by substrate-­‐level phosphorylation Figure NADH. Therefore, less H+ builds up in the inter mitochondrial space and produced in glycolysis and the Kreb’s Cycle. less energy is created.

They also depend on the 4 ATP created by FADH2 per glucose molecule, another co-­‐ enzyme that is transported through Protein Cause: Sight Deterioration Complex VI. Finally, some ATP is created from NADH through Protein Complex V, but very The loss of central vision in LHON cases is caused by little. 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.

Normal eye LHON eye 6

Diagnosis If 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).

Treatment Unfortunately, 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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Research LHON 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.

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”).

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”)

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

Assistive Technology

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.

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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LHON Costs Table Treatment/Service Optometrist

Cost ($) 18 and under: visits are covered by OHIP 18 and older: approximately $120/ appointment

Counselling

Community counselling services: Free Hospital counselling services: Free and a referral by a doctor is usually required Private counselling services: $50- $240 / hour

Assistive Technology

CCTV and ALADIN screen magnifiers: up to $3 000 Apple products (iPad): $259- $800 E-books: Free through public library systems or $15$25 each at book stores.

Portable Electronic Magnifier: up to $600 Computer Software (ZoomText, JAWS, Kurzweil): up to $400

Idebenone

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

LHON Outreach Connecting 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”).

Argentina Facebook Group: https://www.facebook.com/groups/586585178062529/ Canada Facebook Group: https://www.facebook.com/groups/577647358984474/ Finland Finnish Federation of the Visually Impaired: http://www.nkl.fi/7

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France Ouvrir les Yeux: http://www.ouvrirlesyeux.org Germany Facebook Group: https://www.facebook.com/groups/414613055222957 Italy Facebook Group: https://www.facebook.com/groups/ChiaraBerni/ Netherlands Facebook Group: https://www.facebook.com/groups/615379848498198/ Spain ASANOL: http://www.asanol.com Sweden LHON Eye Society and Facebook Group: http://www.lhon.se International Facebook Group: https://www.facebook.com/groups/29805437752

Continuing Research I 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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