Leber optic atrophy

from Wikipedia, the free encyclopedia
Classification according to ICD-10
H47.2 Optic atrophy
ICD-10 online (WHO version 2019)

The Leber's optic atrophy (synonym: liver's hereditary optic neuropathy ( LHON ), Leber's hereditary optic neuropathy, Leber's hereditary optic atrophy, optic nerve damage or liver) is a rare neurodegenerative hereditary disease of the ganglion cells of the optic nerve and belongs to the group of mitochondrial disorders . An initially often unilateral severe visual acuity loss up to blindness in one eye is usually followed by the other eye within weeks to a maximum of nine months. Occasionally, extra-ocular symptoms also occur, which is sometimes referred to as "LHON plus".

Optic neuropathy should not be confused with Leber's congenital amaurosis , a severe, progressive retinal degeneration in infancy and childhood.

history

Optic neuropathy was named after the German ophthalmologist and scientist Theodor Karl Gustav Leber , who first described the disease at the end of the 19th century.

It was the first disease in which a mitochondrial mutation was recognized as the cause.

frequency

The frequency ( prevalence ) is around 1: 50,000. Other sources speak of 1: 100,000. The disease usually occurs between the ages of 15 and 35 years. Men are affected 2.1 to 7.7 times more often than women. Symptoms are very rare in children.

root cause

Optic neuropathy is hereditary and is only transmitted by women ( maternally ), but up to 50% of those affected have no cases in the family; there is a new mutation.

There is a gene mutation in one of the mitochondrial genes that encode the protein subunit of NADH dehydrogenase . The respiratory chain in the inner membrane of the mitochondria is used by the human cell to generate energy, by means of electron transport and a redox reaction, energy in the form of adenosine triphosphate (ATP) is made available and oxygen is consumed.

One of the three most common point mutations is found in 95% of patients . The exchange of guanine for adenine at position 11778 (m.11778G> A) is the most common. The other two mutations are an exchange of guanine for adenine at position 3460 (m.3460G> A) and an exchange of thymine for cytosine at position 14484 (m.14484T> C). All of these mutations lead to a reduced production of ATP and thus to a lack of energy in the cell. In the latter mutation (m.14484T> C), penetrance often appears to be reduced and this mutation is the only one rarely associated with spontaneous remission after one to two years.

Since most of the mutations are "homoplasmic", that is, they occur in all body cells, genetic diagnostics can be carried out on a blood sample. If there is a corresponding suspicion, either a targeted search in the mitochondrial DNA takes place, or a complete sequencing of the mitochondrial DNA.

The mutation alone is necessary, but not sufficient for an outbreak of disease, and other non-genetic factors appear to play a role. These include the number of mitochondrial DNA copies, the haplotype , and cell nucleus modifiers, but also possibly environmental factors such as alcohol consumption , tobacco consumption and other toxic exposures. Sex hormones levels may also play a role. It is believed that these factors lead to an increase in " free radicals " with a decrease in intracellular ATP production and an interruption of the redox equilibrium, ultimately triggering apoptosis of the retinal ganglion cells and degeneration of the optic nerve.

Clinical picture

In the course of the disease, retinal ganglion cells and nerve cells of the optic nerve decline ( degeneration ) . Initially, this usually leads to a reduced perception of the colors red and green and later to central visual field defects (scotoma) with a corresponding loss of visual acuity and sooner or later to blindness . Through the central scotoma, patients often try to look at an object with parafoveolar retinal sites, which gives the impression that they are looking past the object.

In the acute stage, fundoscopy shows a peeled optic nerve papilla , as is also found in other diseases of the optic nerve and can often lead to an initial misdiagnosis and treatment. In the further course of the disease, hyperemia, dilation of the arterioles, tortuous vessels and peripapillary telangiectasias develop . The perimetric examinations show a clear central color scotome for red and green, followed by a relative, later absolute central scotome for white. The primary degeneration of the retina and the optic nerve can lead to secondary changes in the optic tract and in the lateral geniculate body .

The derivation of a sample VEP generally does not provide any significant stimulus responses for any sample size.

Magnetic resonance imaging often only shows a hyperintense image of the posterior parts of the optic nerve.

A complete loss of visual acuity can already be present at the onset of the disease or develop continuously over a period of up to two years. The prospect of restoring visual acuity is slim. The final visual acuity, which occurs after a maximum of about two years, is around 2–5 percent. Eyesight can rarely recover spontaneously, which is usually associated with an m.14484T> C mutation. Such recovery occurs between one and two years after the onset of the disease.

In about half of the cases, Leber's optic atrophy begins unilaterally and then affects the other eye over a period of days to months.

In severe cases, additional neurological symptoms can occur. These include motor movement disorders , changes in the white matter of the brain in the central nervous system (due to the loss of glial cells ), which can be particularly noticeable in magnetic resonance imaging. Also muscular weakness , sensory disturbances , lactic acidosis and other typical "mitochondrial" symptoms as with other mitochondropathies may occur. If such “extraocular” symptoms are present, the term “LHON plus” is sometimes used.

Diagnosis

The diagnosis is based on the clinical picture and requires molecular genetic evidence of the point mutation. It is not uncommon for retrobulbar neuritis to be assumed at the onset of the disease . The diagnosis is often made late and only at specialized neuro-ophthalmological centers.

Differential diagnostics

In terms of differential diagnosis , the clarification of optic neuritis in connection with multiple sclerosis by a neurologist is important. However, toxic and nutritional optic neuropathies triggered by malnutrition, anterior ischemic optic neuropathy (AION), optic hypoplasia, autosomal dominant optic atrophy (ADOA), neuromyelitis optica (NMO), Rosenberg- Chutorstein-Weinstein 's syndrome and the Rosenberg- Chutorstein-Weinstein syndrome must also be distinguished -Bresnick Syndrome .

therapy

Since October 2015, the active ingredient idebenone (trade name Raxone, manufacturer Santhera Pharmaceuticals ) has been available in Germany for the treatment of visual disorders in adults and adolescents from 12 years of age who suffer from LHON , after it was approved by the European Commission in September 2015 . The drug is not approved in the United States. The short-chain active ingredient is said to act as a coenzyme Q analog and bypass complex I of the respiratory chain (and its malfunction), whereby the electrons are transferred directly to complex III.

In addition, numerous dietary supplements and drugs are proposed to modify the course of the disease or to delay an onset of the disease, since other factors play a role in the onset of the disease in addition to the mitochondrial mutation. It is particularly recommended to refrain from alcohol consumption and smoking. Most “modifiers” aim to increase the number and size of intracellular mitochondria or to prevent oxidative damage.

Since the degeneration is not inflammatory , anti-inflammatory drugs are also ineffective ; glucocorticoids in particular do not lead to clinical improvement.

Gene therapy approaches are in development, but so far only for the most common mutation (m.11778G> A). In this case, with an attempt is made adenovirus -associated vector intact mitochondrial NADH genes by intravitreal inject injections and to obtain such a reflectance of the low vision.

Since optic neuropathy is maternally inherited, genetic counseling should be given after the diagnosis and it should be recommended that siblings, mother and other female relatives also be tested. In the case of women, their children should also be included and family counseling should take place.

Web links

Videos

literature

  • Albert J. Augustin: Ophthalmology . Springer Verlag, Berlin 2007, ISBN 978-3-540-30454-8 .
  • A. Hufschmidt, CH Lücking, S. Rauer: Neurology compact. Book and CD-ROM: guidelines for clinic and practice . Thieme-Verlag, 5th edition, 2009, ISBN 978-3-13-117195-5 .
  • B. Leo-Kottler, B. Wissinger: Liver optic neuropathy. In: The ophthalmologist. 108, 2011, pp. 1179-1194, doi: 10.1007 / s00347-011-2482-y .

Individual evidence

  1. ↑ a b c d e f g h i Marcelo Matiello, Amy F. Juliano, Michael Bowley, Amel Karaa: Case 21-2019: A 31-Year-Old Woman with Vision Loss . In: New England Journal of Medicine . tape 381 , no. 2 , July 11, 2019, p. 164-172 , doi : 10.1056 / NEJMcpc1900597 .
  2. ↑ Leber's optic atrophy.  In: Online Mendelian Inheritance in Man . (English)
  3. ↑ Leber's optic atrophy. In: Orphanet (Rare Disease Database).
  4. ↑ Guideline No. 25 of the Federal Association of Ophthalmologists in Germany (BVA) and the German Ophthalmological Society (DOG) : Hereditary retinal, choroidal or visual pathology diseases
  5. ^ A b Rudolf Sachsenweger : Neuroophthalmology . Thieme Verlag, Stuttgart; 3rd edition, (January 1983), page 110 ff. ISBN 978-3-13-531003-9 .
  6. ^ Retina Science - Hereditary Retinal Dystrophies
  7. ↑ Summary of the European public assessment report (EPAR) for Raxone , der EMA, accessed on November 18, 2015
  8. ↑ Summary of the EPAR for the public of the EMA (German), accessed on November 18, 2015
  9. ↑ Santhera receives European marketing authorization for Raxone® in liver hereditary optic neuropathy (LHON) , PM Santhera from September 9, 2015, accessed on November 18, 2015