Friedreich's ataxia

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Classification according to ICD-10
G11.1 Early onset of cerebellar ataxia
- Friedreich's ataxia (autosomal recessive)
ICD-10 online (WHO version 2019)

The Friedreich's Ataxia ( Crohn Friedreich ) is a degenerative disease of the central nervous system . The first symptoms usually appear before the age of 25. The disease is progressive and its symptoms can remain stable for years. This includes a wide range of neurological , psychological , orthopedic and cardiological symptoms.

Friedreich ataxia was named after the German pathologist Nicolaus Friedreich , who first documented the disease in Heidelberg in 1863 .

Epidemiology

In Central Europe, Friedreich's ataxia occurs in an average of one in 50,000 newborns. It is comparatively common and makes up about half of all hereditary ataxias (hereditary forms of ataxia ). It is estimated that around 1,500 people with Friedreich's ataxia live in the Federal Republic of Germany .

The Friedreich's ataxia is one of the autosomal - recessive hereditary diseases . Accordingly, the probability is 25 percent that a child of two heterozygous carriers will inherit the disease. The frequency of heterozygous carriers is estimated at 1:60 to 1: 120.

genetics

Friedreich's ataxia is inherited as an autosomal recessive trait. The associated gene was first localized in 1988 by Susan Chamberlain's group . Molecular genetic testing has been possible since 1996.

The FXN gene is located on chromosome 9 ( gene locus : 9q13-21.1) and codes for the protein frataxin, which is localized in the mitochondria . Other loci may in mutation the symptoms of ataxia mimic, for example, the gene FRDA2 (locus: 9p23-p11).

In the region of the first intron of the gene which is repeat expansion of a GAA - triplets in front, from 82 repeats causing the disease. Accumulations between 40 and 82 copies ( premutations ) carry the risk of Friedreich's ataxia in subsequent generations. The pre-mRNA lengthened by the expansion prevents effective splicing and the protein cannot be produced correctly.

Further mutations of the gene are possible - for example a point mutation - but the documentation of their frequency and the probability with which they trigger the disease is extensive.

root cause

Based on various studies, it is assumed that Friedreich's ataxia is a result of oxidative stress that is triggered by an excess of iron . By observing various yeast cells, it can be confirmed that the mechanism at work here occurs in an early evolutionary manner. In addition, the same mutations were found in the yeasts. An increased iron level can be ascertained, a muscle biopsy shows histologically an increased iron content.

The protein frataxin controls the iron metabolism within the mitochondria of the cell. As a result of the mutation in the sick, the frataxin is not able to cope with the process to a sufficient extent. Free iron ions form ROS within the mitochondria .

pathology

Friedreich's ataxia is characterized by progressive sclerosis of the posterior cord tracts and the conduction tracts between the spinal cord and the cerebellum . In addition, there may be degenerations of the pyramidal tract and the cerebellar cortex as well as cardiac muscle cells .

Symptoms

Friedreich's ataxia usually manifests itself very early in life. The disease begins harmlessly and continues progressively ; it is often not recognized for years. Ataxia and associated disturbances in sensitivity appear early on, which - if at all - are perceived unconsciously; Parents often report a noticeable "penguin walk" as the most noticeable symptom.

The spectrum of symptoms includes:

For people with Friedreich's ataxia, cardiomyopathy is often life-limiting.

A clear diagnosis based on these symptoms is difficult because the above-mentioned constellation of findings can be confused with other neurological disorders. A molecular genetic examination often offers a final guarantee. For this reason, invasive interventions such as muscle biopsy or lumbar puncture have become unnecessary today for additional examinations . In case of doubt, however, the muscle and liver enzymes should be determined in a laboratory by taking a blood sample and, in order to differentiate between vitamin E deficiency ataxia and ataxia telangiectatica, the vitamin E level and alpha-1-fetoprotein (AFP) in the blood serum .

Ongoing symptoms

Through ongoing observation, early therapies can be started and prevent the worsening of these secondary conditions. Are therefore recommended

  • ongoing neurological care,
  • annual cardiological and internal checkups,
  • at least two years of ophthalmological controls,
  • Checks by other specialists if necessary, but then immediately, and
  • regular medical rehabilitation measures.

Thinking, present-day dementia, and changes in personality

The deterioration in the ability to think, the occurrence of pre-existing dementia and increasing changes in character are expressly not among the primary symptoms.

Creeping developments can be favored by the difficult psychological situation and social exclusion.

Differential diagnosis

To be delimited is u. a. the vitamin E deficiency ataxia , the Charlevoix-Saguenay syndrome and SANDO syndrome .

Medical therapy

Effective drug therapy is not permitted. A particular problem with drug therapy - as with many other neurological diseases - is overcoming the blood-brain barrier .

The idea behind this approach is that this disease is based on an underproduction of the protein frataxin . The function of the protein has not been conclusively clarified, but there are strong indications that it is involved in the tasks of cell respiration. It is believed to act as either a chaperone or an iron-binding agent in the formation of iron-sulfur clusters .

Reducing oxidative stress or improving mitochondrial function

By catching the resulting free radicals early , oxidative stress is reduced and mitochondrial function is improved.

In this respect, palliative therapy with radical scavengers is promising and has been confirmed in the laboratory.

Q10 and Idebenone

The effectiveness of the coenzyme Q 10 - analogue idebenone , which was approved in Switzerland for the treatment of Friedreich's ataxia in 2004, is being investigated. Previous studies in this regard, however, have not yet shown any clear improvements in symptoms in sick people compared to control persons and, in the absence of reliable biomarkers, have only indicated that the drug could improve the metabolism within the heart muscle .

Vincerinone / Vatiquinone (EPI-743)

BioElectron (formerly EdisonPharmaceuticals) is actively developing several radical scavengers.

Several phase 2 studies on the use of this preparation for the treatment of Friedreich's ataxia - also for the treatment of Friedreich's ataxia due to point mutation - have shown a significant improvement. No further studies are currently taking place.

Erythropoietin

The administration of erythropoietin has shown that the underlying hormone, in addition to the formation of erythrocytes, also has a neuroprotective effect. The problem is that long-term use can form antibodies that inactivate the active ingredient. Accordingly, an EPO variant was developed that is intended to avoid both disadvantages - the excessive formation of red blood cells and the development of tolerances. The drug is called cEPO and the phase IIa of the clinical study has been completed. The study was unblinded, but the desired efficacy for the treatment of Friedreich's ataxia has not been found and further studies are not intended.

Omaveloxolone (RTA-408)

It was observed beforehand that the Nrf2 signaling pathways are also affected within the affected cells.

The basic functionality has been demonstrated in over 200 peer-reviewed articles.

This synthetic oleanane triterpenoid developed by Reata Pharmaceuticals acts via Nrf2 and activates intracellular and mitochondrial antioxidant signaling pathways as well as other signaling pathways that further improve mitochondrial biogenesis (e.g. PGC1α) and cell metabolism.

Histone deacetylase inhibitors or increase in frataxin production

Evidence has been discovered that the present mutation causes frataxin to be formed correctly and in sufficient quantities, but is denatured during protein folding .

An interruption of the denaturation by histone deacetylase inhibitors (HDACI) or a corresponding increase in frataxin production would then be obvious.

RG-2833 / RGFP-109

RG2833 is a class 1 histone deacetylase ( HDAC ) inhibitor that is supposed to improve transcription - that is, to increase frataxin production and thereby reduce the effect of the cause of Friedreich's ataxia. In the USA , phase I of the clinical study began on March 15, 2012. It is not known if and when the study will end and the results will be published.

Nicotinamide (vitamin B3)

The basic functionality is considered proven; The problem is that nicotinamide, as a hydrophilic vitamin, only has a limited oral bioavailability.

A small study was undertaken by Imperial College. Apparently there are no further investigations.

Alternative therapy strategies

Alternative therapy strategies are currently concerned with supporting the effect of frataxin through stem cell transplantation , gene transfer or the replacement of frataxin.

More therapies

Regular physical treatments help to alleviate orthopedic problems and counteract muscle atrophy . Further occupational therapy is recommended.

Speech therapy should be used to improve pronunciation, swallowing and breathing functions .

The use of walking aids serves to improve the quality of life.

Further symptoms such as cardiomyopathy , archesus or kyphoscoliosis should be treated according to a specialist doctor. In the case of surgical therapies, it is advisable to obtain a second opinion.

history

Friedreich ataxia was first documented in Heidelberg in 1863 by Nicolaus Friedreich from Würzburg , after whom the disease is named. Ataxia ( Greek ataxia , disorder ) describes generally uncoordinated movement of the muscles and disorders of balance . Here the symptom comes to the fore in such a way that the disease is named after it. With his clinical examinations, Nikolaus Friedreich highlighted the disease from the group of atactic diseases that had hitherto been generally understood.

literature

Web links

Individual evidence

  1. ↑ XP Huang et al .: Mitochondrial involvement in genetically determined transition metal toxicity I. Iron toxicity. In: Chem. Biol. Interact. 2006; 163 (1-2), pp. 68-76. PMID 16797509
  2. ↑ Idebenone (Mnesis ® ) approved for the therapy of Friedreich's ataxia  ( page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. , Pharmavista newsletter of June 22, 2004 ( http://www.pharmavista.ch/ )@1@ 2Template: Toter Link / info.multimedica.de  
  3. ↑ Safety and Efficacy of EPI-743 in Patients With Friedreich's Ataxia - Full Text View - ClinicalTrials.gov . ( clinicaltrials.gov [accessed December 12, 2017]).
  4. ↑ EPI-743 in Friedreich's Ataxia Point Mutations - Full Text View - ClinicalTrials.gov . ( clinicaltrials.gov [accessed December 12, 2017]).
  5. ↑ EPI-743 (Vatiquinone) for Friedreich's Ataxia - Friedreich's Ataxia News . In: Friedreich's Ataxia News . ( friedreichsataxianews.com [accessed December 12, 2017]).
  6. ↑ Lundbeck press release - results of the clinical phase IIa study with Lu AA24493 (CEPO) in Friedreich's ataxia  ( page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.@1@ 2Template: Dead Link / www.babelfamily.org  
  7. ↑ pubmeddev: cddo OR RTA 408 - PubMed - NCBI. Retrieved December 12, 2017 .
  8. ↑ Friedreich's Ataxia Treated With Vitamin B3 in Clinical Trial . In: Friedreich's Ataxia News . January 28, 2015 ( friedreichsataxianews.com [accessed December 12, 2017]).
  9. ↑ P. Rustin et al .: Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial. In: Neurology. 2004; 62 (3), pp. 524-525.
  10. ↑ L. Schols et al.: Therapeutic strategies in Friedreich's ataxia. In: J. Neural. Transm. 2004; (68), pp. 135-145.