What is LHON?

Leber’s Hereditary Optic Neuropathy, or simply LHON, is a mitochondrial genetic condition that affects mainly the optic nerve, which can lead to vision loss on the affected person.

foto comparativa - a primeira simula uma visão saudável que enxerga duas crianças com bolas coloridas, e a segunda a visão de uma pessoa com LHON, enxerga a imagem embaçada

comparative photo – the first one simulates a healthy vision that sees two children with coloured balls, while the second simulates the vision of a person with Leber’s Hereditary Optic Neuropathy – LHON, who sees a blurry image.

Vision loss occurs, in most cases, in a spontaneous and painless form, reaching the central region of the visual field. On the manifestation’s classic pattern, only one eye is affected at first and, after eight weeks approximately, the other eye is affected. However, variations of this pattern may occur. After the acute stage, a serious visual loss remains in both eyes. Central visual loss prevents the performance of daily activities such as the reading of texts with a standard size font, driving motor vehicles, and recognising faces. Nevertheless, the peripheral vision is less affected, which means that the affected person can keep certain independence.

Campo visual de escala cinzenta, 3 meses após o início da perda visual, mostrando escotoma centrocaecal (perda da definição da imagem). Após 3 meses, em geral, a pessoa vivendo com Neuropatia Ótica Hereditária de Leber-LHON pode começar a perder a visão central.

Visual field grey scale plots, 3 months after visual loss onset, showing centrocaecal scotoma (image definition loss). After 3 months, in general, the person living with Leber’s Hereditary Optic Neuropathy – LHON may start to lose central vision.

Image link: https://www.nature.com/articles/6700362/figures/1, access on 12th June 2020.

As the individual affected by Leber’s Hereditary Optic Neuropathy – LHON often “does not seem blind”, people around them do not perceive how deep is the vision loss.

This video filmed at the LHON Conference of 2018 offers a broad perspective, including answers for the majority of common questions on scientific/medical matters of LHON, of two medical researchers of the subject:

Leber’s Hereditary Optic Neuropathy – LHON

Further explaining Leber’s Hereditary Optic Neuropathy – LHON

A challenge faced by people living or coexisting with Leber’s Hereditary Optic Neuropathy – LHON is the lack of available information on the disease. This section will help you understand some basic questions on this rare condition.

Note: This section was recently expanded with information on the most recent research about LHON and LHON Plus. Some points may seem very technical for the general public, so support us to improve the accessibility of this section, and please send your question here.

Socially, many times, blindness is perceived as an absolute, all-or-nothing condition. The stereotypes that come to the mind can vary: it goes from the person accompanied by a guide dog, to the person with a cane, or even to a person reading in braille. Leber’s Hereditary Optic Neuropathy – LHON is a condition that does not imply perceivable restrictions of mobility or daily activities, which means that the person living with LHON does not have any physical trace that someone may easily notice.

Besides that, as the condition occurs, in its majority, during young adulthood and adulthood, a great part of the affected already knows how to read and write when they are affected. Moreover, vision loss may not be total; those living with Leber’s Hereditary Optic Neuropathy – LHON generally have peripheral vision, so they tend to use their remnant vision to see and perform their daily activities. This means that people living with LHON constantly need to explain they have a visual impairment. Nonetheless, even though the person living with LHON can normally perform many activities, they will have difficulties in several situations apparently simple for a person with no impairment. As an example, there are social situations where the person may not recognize people around them, read the identification of streets or buses, read the restaurant’s menu, etc. Hence, the person living with Leber’s Hereditary Optic Neuropathy – LHON is commonly identified as someone with partial vision.

Learn more about the different forms of vision loss and its impact on disabled people’s lives in this article, which describes the characteristics of the visually impaired people that participated in the Vision Rehabilitation Groups. The research concludes that the main causes of visual impairment were diabetic retinopathy, glaucoma, optic neuritis, and keratoconus. Some functions and body structures, performance and capabilities on the activities and participation, and environmental factors facilitators or limiters were emphasised, which allowed the description of the characteristics of each participant through the functionality and the improvement of the therapeutic planning. Assistive technologies, optical and non-optical aids used, and their day-to-day benefits were presented. An important conclusion of the article is that vision loss, to any degree, led to functional impairments, which limited and restricted the participation and performance of daily activities, therefore intervening with the individual’s independence, autonomy, and quality of life. However, the use of optic and non-optic aids, and environmental adaptations proved to be beneficial in increasing functionality, showing the influence of external factors on the performance. Knowing and recognizing that diversity within the visual impairment universe exists allows us to understand who the treated individual is, which avoids generalization by the visual condition. Especially for those that coexist with someone affected by a condition such as LHON and LHON Plus, it is important to acknowledge the difficulties that come from the partial vision loss; accepting that the person with impaired vision is not “pretending not to see” or “increasing” the impossibilities. Relatives’ support and acknowledgement are essential so the person affected feels they can overcome the hardships of the disease.

Source: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0034-72802014000500291&lang=pt , access on 12th June 2020.

One of the most frequent questions that patients affected by LHON and their relatives have to answer is if people living with Leber’s Hereditary Optic Neuropathy – LHON could be cured with surgical intervention or a transplant. It is important to explain that there are three key aspects of the human being’s visual system. This system, or group of vision organs, is composed of three elements: the eyes, the brain, and the optic nerve. In LHON’s case, the eyes and the brain function normally. Therefore, the problem is on the optic nerve functioning, which functions similarly to a wire that transmits information from the eye to the brain. On LHON, the optic nerve cells suffer from a process called apoptosis – premature cellular death – which causes the optic nerve atrophy. It is like a TV cable that was damaged. In case they suffer apoptosis, the optic nerve cells normally cannot regenerate.

Cause

It is a condition caused by a genetic mutation in the mitochondrial DNA.

The most common LHON mutation is the 11778 mutation, responsible for about 60% of all LHON cases. In second place, people are affected by 14484 mutation or 3460 mutation, whilst about 5-10% of cases are one of many remaining and very rare mutations. It causes visual morbidity amongst young adults and it is the result of mitochondrial dysfunction. The primary mitochondrial DNA (mtDNA) mutations affect the respiratory chain complexes. The selective vulnerability of the retinal ganglion cells (RGCs) is a key pathological feature and understanding the fundamental mechanisms that underlie RGC loss is a prerequisite for the development of effective therapeutic strategies, which are currently limited.

To learn more visit: https://jmg.bmj.com/content/jmedgenet/46/3/145.full.pdf

Transmission

The genetic mutations that may originate Leber’s Hereditary Optic Neuropathy – LHON are transmitted by the mother to the children. Therefore, the mutation affects men and women differently. Men with an LHON mutation may develop the disease, but never transmit it to their children. Women transmit the affected gene and may develop the disease, though less frequently than men. Those that lost their central vision due to LHON are referred to as “affected”; those with an LHON mutation in their mitochondria, but without vision loss, are called “carriers” or “unaffected carriers”.

There is a clear pattern of genetic inheritance on Leber’s Hereditary Optic Neuropathy – LHON. The mother with affected mitochondrial DNA transmits to her children. This way, people with a family member on the maternal inheritance lineage with an LHON mutation should expect that a sudden, painless loss of central vision they suffer is probably caused by LHON. However, carrying the LHON mutation does not necessarily mean that the carrier will lose central vision. In fact, the majority of LHON mutation carriers do not develop the symptoms. Only about 50% of men and 10% of women that carry the LHON mutation lose vision. Those that are not aware of any family members with Leber’s Hereditary Optic Neuropathy – LHON may be surprised at the onset of symptoms.

Types of LHON

G 11778

TQ4484c

G3460

Other types

How many people are affected?

As it is a rare condition and not much investigated, Brazil does not have a registration database of people living with Leber’s Hereditary Optic Neuropathy – LHON. In the United States about 100 people lose central vision due to LHON every year, joining about 4.000 Americans who already have visual impairments due to LHON. Moreover, thousands of people carry a LHON genetic mutation and may lose their vision at any moment. It is estimated that about 35.000 people in the whole world had vision loss due to LHON. Normally, LHON affects men around the age of 15 to 25 years. Women tend to be affected on a more diverse age gap. Nonetheless, vision loss caused by Leber’s Hereditary Optic Neuropathy – LHON may happen at any age, therefore, if you have an LHON mutation, you may be affected at any point in your life.

Currently, the Reconvexo Institute has registered and supported many people around the globe living with Leber’s Hereditary Optic Neuropathy – LHON.

Diagnosis

Before getting a diagnosis that identifies LHON or LHON Plus, the person affected will go through different stages, from suspicion to confirmation. It is very likely that many doctors are consulted and that many exams are made.

It is easier to get a diagnosis in some cases, like when there is a known family history of genetic mitochondrial disease. This means that if someone in your family is affected by such disease, the path to the diagnosis can be a little shorter as the doctor may use the family history to direct the search for possible diseases related to the symptoms.

However, without a family history, things tend to be different between the onset of the symptoms and the diagnosis of the disease.

Moreover, even if there is a suspicion of LHON, the surge of typical optic nerve alterations, such as the ones described on this site, may lead to a provisional diagnosis. Nonetheless, Leber’s Hereditary Optic Neuropathy – LHON is confirmed with genetic testing.

Another problem is that if the patient is diagnosed only on the late phase of Leber’s Hereditary Optic Neuropathy – LHON, the identification of the disease may be even harder, as in this phase the person may present optic atrophy or nerve head pallor, symptoms that may also be present in other conditions of visual impairment. In this section, we explain some of the exams and phases that the person with LHON may go through starting from the onset of symptoms, going to the suspicion of LHON, and getting to the final diagnosis that confirms the disease.

LHON is a rare thing

Since Leber’s Hereditary Optic Neuropathy – LHON is a rare condition, the medical expert normally suspects of, tests and treats for other vision loss causes and by exclusion defines the diagnosis of LHON. To make sure that a person is affected it is necessary to make many exams. The first indicated exam is an MRI that can discard the possibility of a brain tumour. Another diagnosis that must be discarded is optic neuritis. As vision loss, generally, starts in only one eye, the provisional diagnosis is often of optic neuritis (optic nerve inflammation). Thus, it is normal that the doctor prescribes treatment with corticosteroids for some days. If vision does not improve and the second eye is also affected, the doctor will request more tests such as the Visually Evoked Potential and the Lumbar Puncture to discard other possible causes of sudden and bilateral vision loss – that is when, with no apparent cause, the patient starts to lose the capacity to see.

Evoked potentials

The Evoked Potentials are a set of neurophysiological tests of the nervous system that evaluates nerve fascicles/nerve tracts of the Central and Peripheral Nervous System.

The physical examination of the person living with Leber’s Hereditary Optic Neuropathy – LHON presents optic nerve with peripapillary telangiectasia and pseudo-oedema aspect. These alterations can only be seen by the neuro-ophthalmologist. In this sense, even if the patient’s regular doctor has asked for the exam, another expert will be needed to read and to interpret the results. The expert will be the one to direct the patient for the next diagnosis phases.

As it has been said, the visual acuity may be slightly reduced in the initial stages of LHON, but in general, it will progress and then the affected individual will present certain difficulties, such as to count their fingers with one or both eyes. Between the moment one eye presents symptoms and the moment the other eye starts to be affected, an afferent pupillary defect can be noticed when the disease’s activity is asymmetrical. At this point, colour tests show a reduction of red-green discrimination. Ocular motility, ocular movement, and visual stimuli perception are typically intact and the confrontational visual fields can show an intact peripheral vision. However, central or cecocentral scotomas can be described and more clearly outlined with formal visual field tests. In people with symptoms in only one eye (unilateral), formal visual field tests may present subclinical visual impairments that other exams had not caught. Reduced contrast sensitivity (people have more difficulty in seeing with less contrast) and the subnormal electroretinogram (a test that measures the activity of the retina in response to light stimuli) are also present.

The anterior segment exam with a slit lamp is generally normal. The dilated fundus examination may be normal or reveal hyperemic (an active process where a larger than needed amount of blood is taken to a certain area) “pseudo-oedema” (they appear to be swollen in the image) optic nerves with peripapillary telangiectasia (small vessels around the optic disc). Tortuous retinal arterioles may also be present. Although optic nerve heads may seem hyperemic and swollen, they do not present escapes on fluorescein angiography, differently from those affected by inflammatory diseases. This means that this exam may indicate to the expert that another condition is discarded, which may lead to another exam, the genetic testing, which will lead to the final diagnosis.

Other exams, tests, and procedures on the path to a diagnosis

Angiography or angiogram is a method to perform radiography of blood vessels by injecting a radio-opaque contrast agent into the intravascular environment.

The fluorescein angiography may be performed to discard real oedema on the optic nerve. This happens because on this exam, on LHON’s case, dye escapes are not observed along the optic nerve head edges that would be swollen otherwise.

Optical Coherence Tomography (OCT) is a new imaging technology based on low-coherence interferometry, which uses optical scattering of near-infrared light as a signal source to provide vascular transverse images with a higher resolution than any other available technique. It has the capacity of providing understanding to many stages of atherosclerosis and the vascular response to treatment, which provides a solution close to histology. The images obtained by OCT allow doctors to visualise and measure important characteristics of the vessels for the stent placement.

Optical Coherence Tomography (OCT) of the optic nerve may show an elevation on the early stages of the disease or atrophy on late stages.

One of the most important tests performed by those living with Leber’s Hereditary Optic Neuropathy – LHON is the visual field test, which detects the area extension that your eye can capture images and where it does not have this capability anymore. Those living with LHON tend to have what is called central scotoma: an area at the centre of the visual field where no information is transmitted from the eye to the brain.

The visual field campimetry is made with the patient sitting with their face near to the measuring device, called campimeter, which emits flashes of light in different places and with different intensities on the patient’s visual field.

During the test, a light at the back of the device is emitted and the patient must keep focusing on it. This way, the person will have to ring a bell on their hand as they are able to identify new flashes of light, but without looking around, finding the lights using only peripheral vision.

 

Campimetry is an exam that evaluates vision impairments and visual field areas with no vision, indicating if there is blindness in some area of the eye, even if the patient does not notice the problem.

Below there is a campimetry of a person living with Leber’s Hereditary Optic Neuropathy – LHON with four years of symptoms:

campimetria de uma pessoa vivendo com Neuropatia Ótica Hereditária de Leber- LHON com quatro anos de sintomas.
campimetria de uma pessoa vivendo com Neuropatia Ótica Hereditária de Leber- LHON com quatro anos de sintomas.

Optical Coherence Tomography – OCT

Another important test is the OCT (Optical Coherence Tomography). This test measures the thickness of the optic nerve. Generally, the optic nerve is extraordinarily thick when the vision loss starts, because the fibres are swollen. Later, the nerve becomes extraordinarily thin as the fibres atrophy.

The evaluation of the retinal nerve fibre layer has major importance on the diagnosis and the follow-up of many anterior visual pathway diseases.

Representação esquemática da camada de fibras nervosas da retina originárias da hemirretina temporal (em sul) e aquelas da hemirretina nasal (em vermelho)

Figure 1: Schematic representation of the retinal nerve fibre layer originated from the temporal hemiretina (in blue), and those from the nasal hemiretina (in red).

In this article, you may check out all of the information about OCT, and the main clinical and instrumental analysis methods of the retinal nerve fibre layer: (https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0034-72802012000200010)

Next, we have reunited the main findings on anterior visual pathway diseases including inflammatory, ischemic, toxic, hereditary, compressive, and traumatic lesions of the optic nerve, optic chiasm lesions, optic tract lesions, and lateral geniculate body lesions, which are common on the condition of those living with LHON and LHON Plus.

This exam can describe the changes in the retinal ganglion cell complex (GCC) concerning the retinal nerve fibre layer (RNFL) over time on people with Leber’s Hereditary Optic Neuropathy – LHON.

Optic nerve with peripapillary telangiectasia and pseudo-oedema aspect

Foto do nervo óptico de pessoa que vive com Neuropatia Ótica Hereditária de Leber após 1 ano de diagnóstico de Neuropatia Ótica Hereditária de Leber LHON.

Photo of the optic nerve of a person living with Leber’s Hereditary Optic Neuropathy – LHON one year after the LHON diagnosis

The high-definition optical coherence tomography (OCT) shows the events occurring at the optic nerve head in Leber’s Hereditary Optic Neuropathy – LHON.

As a result of a diffuse axonal injury, brain and optic nerve cells may die, causing swelling and increasing area’s pressure (intracranial pressure). The increased pressure may worsen the injury by decreasing blood supply to the brain or the optic nerve.

The axonal injury occurs before and during the time of vision loss.

 

The OCT exam detects the retinal nerve fibre layer (RNFL) atrophy after the acute event, which in most cases is restricted to the maculopapillar bundle (a fascicle of nerve fibres that starts at the macula lutea and ends at the optic disc). A new OCT algorithm allows the identification and measuring of the ganglion cell complex (GCC).

Ganglion cells compose the only output of retina’s visual information, since its axons combined form the optic nerve. This type of cell receives direct signals from bipolar and amacrine cells forming what are called synaptic triads.

OCT in people with Leber’s Hereditary Optic Neuropathy – LHON shows where the GCC alterations fit on the chain of events since the initial acute phase until the late acute and chronic phases, concerning visual acuity, visual fields, and fundoscopy findings.

 

Sometimes, the diagnosis of those living with Leber’s Hereditary Optic Neuropathy – LHON may be a challenge, especially when the fundus typical findings of the retinal nerve fibre layer such as swelling and telangiectasia are not apparent. The GCC changes related to the RNFL we have identified may be useful on the early diagnosis of those living with LHON.

Source: Barboni P, Savini G, Valentino ML, Montagna P, Cortelli P, De Negri AM, Sadun F, Bianchi S, Longanesi L, Zanini M, de Vivo A, Carelli V.. Retinal nerve fiber layer evaluation by optical coherence tomography in Leber’s hereditary optic neuropathy. Ophthalmology 2005;112:120–126.  

https://www.ncbi.nlm.nih.gov/pubmed/15629831

GENETIC TESTING

Only genetic testing, made by blood or saliva may determine if someone carries an LHON mutation. Some laboratories test only for the three most common LHON mutations. Others, like GeneDx on the United States, test for twenty LHON mutations, which includes many of the very rare mutations. By clicking here you will see the list of medical centres in Brazil that perform exams and the follow-up of people living with Leber’s Hereditary Optic Neuropathy – LHON

 

Important information is that when a family member receives a genetic testing positive result, certainly all of those on the maternal lineage are going to have the same mutation. This fact exempts the remaining members of the maternal family from doing the test.

Genetic testing is a type of medical test that identifies changes on the chromosomes, genes, or proteins. The results of genetic testing may confirm or exclude the suspicion of a genetic disease or help to determine the hypothesis about a person developing or transmitting a genetic disease. Currently, more than a thousand genetic tests are being used to diagnose genetic diseases and conditions, and Leber’s Hereditary Optic Neuropathy – LHON is one of those genetic conditions confirmed by genetic testing.

What to do?

The moment a person suffers vision loss, they must consult an ophthalmologist. After confirming the LHON mutation diagnosis, the person must consult a neuro-ophthalmologist, medical expert that deals with the optical nerve. It is important to notice that the disease conditions are so rare that many doctors are not up-to-date about the developments of recent therapies and treatments for LHON. These types of research are still very scarce in Brazil. However, many neuro-ophthalmologists and medical centres (link) follow great research centres around the world which research Leber’s Hereditary Optic Neuropathy – LHON. In Brazil, many medical centres assist patients with LHON. 

We have put together some of them that may assist you.

Treatment

Whenever there is a suspicion of Leber’s Hereditary Optic Neuropathy – LHON, the person must consult a neuro-ophthalmologist.

Since LHON causes optic nerve atrophy, an expert on this field probably has experience with the disease. Click here to find a medical centre on our guide.

In most countries, including Brazil and the USA, there is no approved treatment for Leber’s Hereditary Optic Neuropathy – LHON. In Europe, a product developed by Santhera Pharmaceuticals called Raxone was approved by European Medicines Agency (EMA) for utilisation on early-stage LHON. Raxone is the pharmaceutical grade of idebenone, a synthetic form of coenzyme Q10.

 

Many European countries and Israel decided to offer to and to pay for Raxone for people living with LHON that met certain criteria. The main clinical trial that led to this approval is reproduced here:

On the European public assessment report’s summary concerning Raxone, it is explained how the European Agency assessed the medicine to recommend its authorisation in the European Union and its conditions of use. Raxone is a medicine used to treat visual impairment in adults and adolescents aged 12 years and over with Leber’s Hereditary Optic Neuropathy – LHON, an inherited disease characterised by progressive vision loss. Raxone contains the active substance idebenone.

As the number of patients with Leber’s Hereditary Optic Neuropathy is low, the disease is considered ‘rare’, and Raxone was designated an orphan medicine ‘ (a medicine used in rare diseases) on 15th February 2007.

Raxone is a ‘ hybrid medicine ‘. , which means that it is similar to a ‘reference medicine’ that contains the same active substance. However, Raxone contains idebenone at a different strength. The reference medicine for Raxone is Mnesis (45 mg tablets).

Raxone can only be obtained with a medical prescription and the treatment should be started and supervised by a doctor with experience in LHON. Raxone is available as 150 mg tablets, and the recommended dose is two tablets taken three times a day with food.

The active substance in Raxone, idebenone, is an anti-oxidant agent that acts on the mitochondria (the structures inside cells that produce the energy necessary for cells to function). Those affected by LHON have mutations (defects) in the genetic material of mitochondria. This means that mitochondria do not work properly to generate energy and produce toxic forms of oxygen (free radicals) that damage nerve cells in the eye that are needed for vision. Idebenone is thought to help improve energy production by restoring mitochondrial function, thereby preventing cellular damage and the vision loss seen in LHON.

Raxone has been investigated in one main study involving 85 patients with LHON, in which it was compared with placebo (a dummy treatment) over 24 weeks. The main measure of effectiveness was vision improvement, mostly based on the numbers of letters patients were able to read on a standard eye test chart. By the end of the study, patients treated with Raxone were able to read, averagely, 3 to 6 letters more compared with patients receiving placebo. Additionally, some patients who were classified at the beginning of the study as ‘off chart’ (unable to read any letters on the chart) were able to read at least one line during the eye test after treatment, which was also considered clinically important. Additionally, 30% of patients treated with Raxone (16 out of 53) had a clinically relevant vision recovery in at least one eye, compared with 10% of patients (3 out of 29) in the placebo group.

Additional supportive data on the benefits of Raxone came from an expanded access program through which Raxone was made available to individual patients who were not participating in a clinical study, and from a case record survey, which included data from patients with LHON who did not receive any treatment. 

The most common side effects with Raxone (which may affect more than 1 in 10 people) are nasopharyngitis and cough; mild to moderate diarrhoea and back pain are also common (affecting up to 1 in 10 people).

For the full list of all side effects and use restrictions with Raxone,  see the package leaflet.

The Agency’s Committee for Medicinal Products for Human Use (CHMP) decided that the benefits of Raxone are greater than its risks and recommended that it be approved for use in the EU.

The Committee noted the lack of treatments for preventing or reversing vision loss in patients with LHON. The results of the main study showed a visual improvement in patients treated with Raxone, and this trend towards a beneficial effect was confirmed by additional data from an expanded access program and a case record survey. Concerning Raxone’s safety, the majority of side effects observed with the medicine were mild or moderate in intensity.

Raxone has been authorised under  ” exceptional circumstances “. This is because it has not been possible to obtain complete information about Raxone due to the rarity of the disease. Every year, the European Medicines Agency will review any new information that becomes available and this summary will be updated as necessary.

Since Raxone has been approved under exceptional circumstances , the company that markets Raxone will conduct additional studies on the long-term effects and safety of Raxone and will establish and maintain a registry of LHON patients treated with Raxone.

A prisk management plan has been developed to ensure that Raxone is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics e and the package leaflet for Raxone, including the appropriate precautions to be followed by healthcare professionals and patients. The European Commission granted a marketing authorisation, valid throughout the European Union for Raxone on 8th September 2015.

For more information about the treatment with Raxone, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

For practical information about the use of Raxone, patients should read the package leaflet or contact their doctor or pharmacist.

The company that developed Raxone continues to evaluate the product through many clinical trials, such as the LEROS study, that searches individuals affected by LHON with one of the three main mutations (11778, 14484, and 3460).

About the Idebenone

In the past, Idebenone was considered a dietary supplement. Some internet suppliers keep providing it on this premise. Because of this, medication supervision agencies, such as the FDA in the USA and ANVISA in Brazil, do not supervise its commercialization. On the other hand, idebenone is not available at regular chemist’s shops, only on compounding pharmacies and websites. At Brazil’s first LHON conference, the doctor Carlos Filipe Chicani described the therapeutic options of Leber’s Hereditary Optic Neuropathy – LHON and the improvements on genetic therapies.

We share here an in vivo study of brain and muscle bioenergetics in a male patient with LHON and mtDNA mutation at 11778 bp who developed spastic paraparesis with white matter lesions on brain MR imaging. The study was performed before and during treatment with idebenone (135 mg t.i.d.) and after withdrawal. Clinical improvement and worsening were associated with bioenergetics parallel changes in the brain and skeletal muscle after the administration or withdrawal of idebenone. Paraparesis’s reversal by idebenone was followed by the normalization of 31P-MRS, serum lactate, and central motor conduction. The extra-ocular neurological dysfunction in LHON may be responsive to treatment by appropriate quinones.

Quinones are compounds of broad natural distribution, distinguished by the presence of quinone rings and divided into three subgroups due to the different aromatic systems that support them; they are the groups of benzoquinones, naphthoquinones, and anthraquinones. These compounds are functional in many live organisms, being found on plants (during the photosynthesis process) and even on the human body (acting on the gut flora and blood coagulation) [1].

Currently, a great variety of compounds of this group is known and this is due to their isomeric content, in other words, the capacity of a quinone compound present, in general, at least one isomer. The chemical and electronic properties of quinones are studied for over a century. It is considered that these compounds have many particularities and their effective participation in a biological process is attributed to their oxidative character. [2] [1].  

Quinones are highly recognized for their anti-tumour, virucide, and microbicide performances, as well as other reasons. On this family, the main derivatives with diverse and effective biological activities are the 1,4-Naphthoquinones, because they become more stable with the bonds on these positions. [1] [3].

On the naphthoquinones group, distinguished by a quinone ring supported by naphthalene rings, many examples of compounds can be presented. Amongst them, the lapachol (found on the bark of tabebuia genus trees) and vitamin K on its many forms (phylloquinone, menaquinone, and menadione). On the benzoquinones group, you can consider the cyclohexadienedione, whose chemical formula is C6H4O2. The two isomers of cyclohexadienedione are orthobenzoquinone (1,2-benzoquinone) and para-quinone (1,4-benzoquinone). The last group, the anthraquinones, has as representatives compounds such as xyloidone, which has a quinone ring supported by anthracene rings.

Source: https://www.jns-journal.com/article/S0022-510X(96)00311-5/fulltext#back-BIB1, access on 24th of June of 2020.

Idebenone is the first medication approved for Leber’s Hereditary Optic Neuropathy – LHON. It is a short-chain benzoquinone, similar to coenzyme Q10.

Coenzyme Q10 is a fat-soluble molecule produced by the human body. It is present on beef, sardine, spinach, and peanut. Ageing, bad dietary habits, stress, and infections affect our capacity to provide adequate quantities of coenzyme Q10. Therefore, supplementation is important for the smooth functioning of our body.

One of coenzyme Q10’s main function is to act as an efficient antioxidant, acting directly against free radicals, destroying the molecules responsible for cardiovascular diseases and precocious ageing.

Coenzyme Q10’s deficiency may cause genetic mutations and nephrotic syndrome.

Coenzyme Q10’s studied benefits

 

1. Cholesterol and triglycerides control:

On 2018, a study with 80 Iranian women, all of them with type 2 diabetes, analysed the effects of coenzyme Q10. During 12 weeks, 100 mg of the substance were administered each day for 36 participants, while the other 44 women received a placebo. The research identified that, on the group that received the supplement, there was a reduction on the insulin resistance, as well as on ferritin, on total cholesterol, and on LDL cholesterol. At the same time, HDL cholesterol increased significantly. In addition, the level of triglycerides in the blood was also reduced on the group that received the supplement.

2. Free radicals’ reduction:

Another study also conducted in 2018, in Italy, analysed 21 young athlete men that received coenzyme Q10 supplementation (200 mg/day) for a month. These participants were compared to another group that received placebos. Before and after an intense exercise session (40 minutes of running) a blood sample from the participants was collected. The results showed that the supplementation caused resistance to coenzyme Q10 deprivation, induced by exercise. Additionally, the substance was associated with free radicals’ reduction and DNA integrity preservation. However, it is important to emphasise that the supplementation was not capable of improving physical performance or reducing muscular damage on athletes.

3. Improvement of bipolar disorder’s depression symptoms:

Bipolar disorder was also an object of analysis amongst coenzyme Q10 studies. According to the study conducted on Iran, there was an improvement in the depression symptoms after eight weeks of treatment with coenzyme Q10 (200 mg per day). The analysis was made with 69 patients with bipolar disorder associated with depressive episode. The patient’s depression degree was assessed based on the Montgomery-Asberg Depression Rating Scale at the beginning of the study, after the fourth week, and, lastly, on the eighth week of said study.

4. Antioxidant action:

On 2019, researchers investigated the effects of coenzyme Q10 supplementation on oxidative stress and the activity of antioxidant enzymes. The study was conducted with volunteers exposed to toxic cadmium, a type of metal harmful to our health. Coenzyme Q10 supplementation with 120 mg daily, compared to placebo, indicated a significant reduction on the oxidative stress and an increase in the antioxidant enzymes activities, such as superoxide dismutase and glutathione peroxidase.

 

How does Coenzyme Q10 act on the organism?

The substance acts on the mitochondria, organelles present on body cells, participating in the electron transport chain during cellular respiration. Nutritionist Felipe Cardoso, Doctor of Nutrition Science by UFRJ (Universidade Federal do Rio de Janeiro) and professor at Faculdade Bezerra de Araújo, explains that this means that coenzyme Q10 controls this electron passage, preventing oxidation, cellular membrane damage, and promoting a great water concentration in the cells. Because of its intracellular location (inside the mitochondria), tissues and organs with greater energetic necessity (such as neurons, muscles, liver, and kidneys) benefit more from its presence.

Unlike coenzyme Q10, Idebenone has distinct properties and action mechanisms. Idebenone is a powerful antioxidant and lipid peroxidation inhibitor. Antioxidants are substances capable of delaying or inhibiting the oxidation of an oxidizable substrate. The role of antioxidants is to protect healthy body cells against the oxidant action of free radicals. It is important to emphasise that it facilitates the electron flow directly to the complex III, ignoring the dysfunctional complex I of the mitochondrial respiratory chain, increasing then the production of adenosine triphosphate (ATP).

Idebenone can, this way, improve the bioenergetic production on the respiratory chain on the event of a defect on the mitochondrial complex.

An increasing published body of evidence indicates that idebenone is efficient and safe for the treatment of patients with LHON.

The treatment with idebenone proved to be effective, safe, and well-tolerated.

In an international consensus meeting on 2016 about the use of idebenone in LHON, it was recommended that patients with LHON should be treated, if within one year from symptoms affecting the second eye, with idebenone 3 × 300 mg/day, for at least a year, and treatment should be continued in responders until a one-year plateau is reached.

In the randomized placebo-controlled clinical trial called RHODOS (Rescue of Hereditary Optic Disease Outpatient Study), 85 patients with LHON were included, in the first five years after symptoms onset, and randomized to either idebenone 900 mg/day for six months or placebo. Idebenone was well tolerated, and even though the prespecified primary endpoint (best recovery in visual acuity) did not reach statistical significance, all secondary endpoints (change in best visual acuity, change of visual acuity of the best eye at baseline, and change of visual acuity in all eyes) showed a trend toward visual recovery in favour of idebenone. This means that more studies would be good for us to get to a better conclusion about the beneficial effects of Idebenone use on patients with LHON. This will only be possible if a political and social effort is made on the sense of pressing authorities to perform due legal approvals for the realisation of more studies. For now, it is important to emphasise that the non-existence of side effects on the use of said medication is a great sign that studies and trials could be made without risk to people’s health. Moreover, an increasing body of evidence indicates that idebenone is effective and safe for the treatment of patients with LHON, including a large retrospective open-label study, several case reports and case series, an expanded access program, and ongoing post-authorization clinical studies.

However, there are still many questions to be answered, which were not properly researched yet.

  1. Ideal treatment duration. A longer treatment period with idebenone may offer additional therapeutic benefit and could lead to significant vision recovery, even if patients have an established disease and severe vision loss at treatment onset. In a large retrospective study, determinants of better prognosis for visual recovery were early initiation of treatment and a longer treatment course. The average time to recovery was around 17 months after starting the idebenone treatment.
  2. Maximum time window from symptoms onset to starting idebenone treatment. Idebenone therapy is likely to have the most impact when started early, as the retinal ganglion cell loss is still minimal in the early phase of the disease. Currently, there is no robust evidence to support idebenone use in patients with long-standing visual loss, and this requires further research.
  3. Leber’s Hereditary Optic Neuropathy – LHON may become symptomatic in children under 10 years and also in patients with late-onset LHON, who are more prone to multiple comorbidities and polymedication. For both groups of patients, robust data are needed on the use of idebenone. Published data on the treatment of children with LHON with idebenone, or older people, consist mainly on case reports.
  4. A biomarker for predicting drug response to idebenone treatment is currently not available and will still require further research.
  5. No studies have been conducted on idebenone use as prophylaxis in asymptomatic mutation carriers of an LHON mutation.
  6. Anecdotal data on idebenone use in patients with Leber’s Hereditary Optic Neuropathy – LHON Plus have been published but are not sufficient to evaluate a possible effect of idebenone on extraocular manifestations. This also applies to the effect of idebenone in patients with LHON + multiple sclerosis (MS)-like disease (“Harding disease”). One patient with LHON and MS-like disease, whose visual acuity improved after six months of treatment with idebenone, was reported by Carelli et al. Concerning the possible effects on new-onset extra-neurological features, a 31-year-old male patient was reported. The man had improvement in spastic paraparesis, which had begun a week before starting idebenone, and no effect on vision loss, which had begun seven years before the start of treatment.

7. Mitochondrial DNA copy number and mitochondrial biogenesis are associated with incomplete penetrance in LHON, with high mtDNA content being associated with unaffected LHON mutation carriers. The mtDNA copy number may be a determinant of conversion to disease in LHON mutation carriers, and influencing mitochondrial biogenesis has been suggested as a potential therapeutic strategy to be further evaluated. It has been recently shown that under specific circumstances, idebenone may have an effect on mitochondrial biogenesis, but further research is required to further elucidate this.

Next steps on the research of Idebenone use on Leber’s Hereditary Optic Neuropathy – LHON

Presently, there are phase IV ongoing post-authorization research studies to assess the long-term efficacy and safety of the idebenone (Raxone®) treatment in patients with LHON.

The LEROS (“External natural history controlled, open-label intervention study to assess the efficacy and safety of long-term treatment with Raxone in patients with LHON”) study is an open-label interventional study on the use of idebenone in patients with LHON up until 5 years of symptoms onset (NCT02774005).

As a control group to the LEROS study, data are being collected on a CRS study (“Historical case record survey of visual acuity data from patients with LHON”), which is an observational retrospective study of a cohort of people living with Leber’s Hereditary Optic Neuropathy – LHON who were not treated with idebenone.

Additionally, a non-interventional study is also being conducted; the PAROS (Post-Authorisation Safety Study with Raxone in LHON Patients) study, which aims to assess the long-term safety profile and the long-term efficacy of idebenone on LHON patients’ treatment when used under conditions of routine clinical care.

The support of people living with Leber’s Hereditary Optic Neuropathy – LHON

The treatment of people living with Leber’s Hereditary Optic Neuropathy – LHON also involves supportive management, including visual aids and rehabilitation, environmental risk factor prevention, such as smoking and excessive alcohol consumption, and early recognition and treatment of psychiatric comorbidities, such as reactive depression.

Other treatments for people living with Leber’s Hereditary Optic Neuropathy – LHON being currently tested on phase III clinical trials

At the moment, there are currently ongoing phase III clinical trials to assess the efficacy and safety of gene therapy of a single intravitreal injection of a viral vector (adeno-associated virus) transporting the wild-type ND4 gene, in patients with LHON caused by the mutation m.11778G>A, in the first year after symptom onset. Randomized, double-masked, sham-controlled clinical trials are ongoing to evaluate the efficacy of a single intravitreal injection of GS010 (rAAV2-ND4) in patients affected by LHON due to the m.11778G>A mutation, in the first 6 months after the first symptom (GS-LHON-CLIN-03A, RESCUE) (NCT02652767) or between 6 and 12 months after the first symptom (GS-LHON-CLIN-03B, REVERSE) (NCT02652780).

Source: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S2326-45942017000100707

Treatment strategies

Recent studies suggest that oestrogen may protect women that carry an LHON mutation. Female carriers of LHON, as well as those affected by the condition, might want to read this article and discuss its implications with their doctors.

LHON and oestrogen article

LHON and oestrogen – video

IMPORTANT NOTICE

Avoid going through “cell therapies” with stem cells to “cure” LHON and other mitochondrial disorders of institutions with no academic and scientific production.

Cell therapy with stem cells is the use of stem cells  to treat or prevent a disease or condition.[1] Since 2016, the only established therapy using stem cells is the hematopoietic stem cell transplant (HSCT)[2] Normally these cells are derived from bone marrow, but they can also derive from umbilical cord blood blood. Many ongoing studies are trying to develop different sources of stem cells, as well as how to apply cell therapies with stem cells to neurodegenerative diseases [3] and conditions such as diabetes and cardiovascular diseases.

Cell therapy with stem cells became controversial after developments such as the capability of scientists isolating and cultivating embryonic stem cells, creating stem cells using somatic cell nuclear transfer and the use of techniques to create induced pluripotent stem cells

This controversy is frequently related to abortion policies and human cloning. Additionally, the efforts to commercialise treatments based on the transplant of blood stored on the umbilical cord have been controversial.

To this moment, some factors that prevent performing genetic therapy are:

  1. It is still impossible for the cells injected on the blood or on the cerebrospinal fluid (liquid around the brain) to reach the place where the retina is located. The retina is the part of the eye responsible for the formation of images, in other words, for the sight sense. It is like a screen where images are projected: it retains the images and translates it to the brain through electric impulses sent by the optic nerve.

 

  1. The ganglion cells are like a type of neuron found on the retina. Ganglion cells compose the only output of retina’s visual information, since its axons combined form the optic nerve. As they are the most complex group of cells on the body, currently, there is no way of turning cells into ganglion cells of the retina, which atrophy on LHON.


3. Reconstruct these cells does not mean anything if they do not know where their axons need to connect to. The axon is the part of the neuron responsible for conducting electric impulses from the cellular body to another distant place, such as a muscle or another neuron.

Precautions

Many experts suggest that those carrying an LHON genetic mutation, be it a carrier or an affected individual, must avoid environmental factors that may create additional stress on the mitochondria. These factors include smoke (of all kinds – wood burning stoves, fire pits/bonfires, cigarettes, smoking pipes, cigars, marijuana, incenses, etc.), alcohol, antimicrobials (erythromycin, ethambutol, linezolide, chloramphenicol, aminoglycoside, tetracycline, and hyperbaric oxygen), quaternary ammonium cations, and Ringer’s lactate solution.

Exercising and a moderate, balanced diet are elements that must be included in the lives of people living with Leber’s Hereditary Optic Neuropathy – LHON. Exercising improves the resourcefulness of the person on their daily activities, helps fighting depression, decreases the typical fatigue on the person with LHON, as well as improves the cellular respiration performance.

Confusions related to the Leber’s Hereditary Optic Neuropathy – LHON condition

As it is a rare and little researched disease, it is not very known by society, by the medical community, and even by the people with this condition themselves. Even the name “LHON” may be confusing! Leber’s Hereditary Optic Neuropathy is frequently referred by its acronym in English: L-H-O-N. However, it is also known simply as “Leber’s”, name of the German doctor that first described the disorder (Theodor Leber). The same doctor also described a completely different ocular condition called Leber’s Congenital Amaurosis, whose origin is also genetic, but affects the retina and not the optic nerve. Both conditions have nothing in common besides the name of the doctor that described them. Because of this, it is important to be sure that you are correctly referring to Leber’s Hereditary Optic Neuropathy – LHON when someone talks about “Leber’s”. This simple information is important, after all, each disease is treated by different medical specialties and have different treatments. In other words, a person with Leber’s Hereditary Optic Neuropathy – LHON must look for a neuro-ophthalmologist; a person with Leber’s Congenital Amaurosis must be followed-up by a retinologist.

Contact

Reconvexo Institute

reconvexo@ireconvexo.com.br

+55 (11) 99547-3306

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