Beta Propeller Protein Associated Neurodegeneration

from Wikipedia, the free encyclopedia
Classification according to ICD-10
G23.0 Hallervorden-Spatz syndrome
ICD-10 online (WHO version 2019)
The WIPI4 protein is a 7-bladed beta propeller. It is encoded by the WDR45 gene and is responsible for autophagy processes.

The beta-propeller protein-associated neurodegeneration ( BPAn ) is a rare disease from the spectrum of NBIA disease control. It is the most common of the NBIA variants, accounting for up to 45% of all cases. BPAN is characterized by developmental delays and epileptic seizures in childhood with movement problems, including dystonia and parkinsonism . It is also referred to in the literature as NBIA5 and Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA). First clinical mentions are from 2012. With a prevalenceout of a maximum of 1/1 000 000 this disease is very rare. In Germany alone, fewer than 20 cases are documented (as of September 2018).

Pathogenesis

In most cases, BPAN is caused by a spontaneous mutation ( de novo ) of the WDR45 gene at Xp11.23 on the X chromosome . In girls, the defect is caused by a dominant , heterozygous inheritance via the germline . In boys there is either a hemizygous inheritance through the germline or a deletion on the WDR45 gene. Mosaics were found in some patients . The mutation is mostly found in girls. It is believed that the genetic defect in boys is so serious that they usually do not survive the embryonic stage. In very rare cases, especially if the mother has a mosaic of genetic changes, BPAN can be inherited from the parents. It can be assumed that the proportion of heredity via germline mosaics generally occurs more often than assumed, so that at least some such cases are incorrectly diagnosed as de novo .

The WDR45 gene encodes the protein WIPI4, which plays an important role in autophagy in the nerve cells of the brain. Because of its special structure with seven wing-like elements, it is called a beta propeller . The mutation impairs the function of this protein. The severity of the impairment is evidently determined by the individual genetic defect. Studies also show that the function of the mitochondria and the lysosome is impaired.

The role that iron-containing waste products accumulated in the nerve cells play in the clinical picture is not fully understood. It is believed that the autophagy affected by the genetic defect dominates the symptoms. In addition to the oxidative and therefore toxic effects of free iron, it is assumed that a lack of bioavailable iron can impair the function of cell organelles such as B. the mitochondria impaired. Medical studies have shown that the reduction of iron in the brain cells does not have a significant impact on the health of patients.

diagnosis

T1-weighted MRI image of the brain of a patient with BPAN (beta-propeller protein-associated neurodegeneration). It shows a hyperintense (bright) halo around a straight band in the substantia nigra and the midbrain dome (arrow). This halo is a diagnostic indicator for BPAN.
T2-weighted MRI sequences showing globus pallidus hypointensity (A) and hypointensity of the substantia nigra (B) (arrows). In BPAN, the substantia nigra is usually more hypointensive than the globus pallidus, which indicates a higher iron content.

Since the symptoms are mostly unspecific, a reliable diagnosis can only be made using imaging methods and genetic sequencing. In the advanced stage, changes in the substantia nigra and globus pallidus caused by the accumulation of iron can be identified by means of magnetic resonance imaging . Early signs prior to detectable iron deposition could include swelling of the substantia nigra and hyperintensity on a T2-weighted MRI image of the dentate nucleus . Ultimately, however, the diagnosis can only be confirmed by identifying the mutation in the WDR45 gene. EEGs are indicated to diagnose the common epilepsy .

Symptoms

The symptoms usually start in early childhood or at birth. The child's general development is impaired from the start. After a stable phase of several years, an increasing deterioration of the cognitive and general condition sets in in early adulthood. The symptoms vary in severity among those affected. They include u. a .:

Most children do not develop a language, but some can formulate individual words or maximally short sentences. The understanding of language, on the other hand, is often better developed. In general, however, communication is difficult as there are also cognitive difficulties in using gestures or learning sign language.

Many people with BPAN have recurrent seizures ( epilepsy ) that begin in childhood or early childhood. Several different types of seizures can occur during this condition, even in the same person. The first thing that often occurs is attacks that are triggered by a high fever. Affected individuals can also have generalized tonic-clonic seizures (also called grand mal seizures). These types of seizures affect the entire body and cause muscle rigidity, convulsions, and loss of consciousness. Other types of seizures that may occur with this condition include brief gaps in consciousness such as the occurrence of absence seizures (also called petit mal seizures), sudden episodes of weak muscle tone (atonic seizures), involuntary muscle twitches ( myoclonic seizures), or more pronounced movements than called epileptic spasms. Some patients have seizure patterns that are similar to those in epileptic syndromes such as West syndrome or Lennox-Gastaut syndrome .

Course of disease

In contrast to most other NBIA diseases, symptoms appear at birth or in early childhood. Because of the mostly unspecific symptoms - especially the developmental delay  - the disease is initially not recognized. Many relatives report that both doctors and those around them often react soothingly. However, with age, the limitations become apparent. The usual development steps occur later or do not occur. Depending on the severity, this can lead to a severe developmental disorder, which manifests itself in a permanent multiple disability and leads to the need for care .

After a phase of hesitant development steps, a status of stagnation sets in. A rapid deterioration in general condition is to be expected around early adulthood. The dystonia and the cognitive decline increase up to dementia. Complications can lead to premature death.

However, it turns out that there is no strictly uniform development of BPAN, so that the exact course of the disease cannot yet be predicted. The various forms can be very different and are currently still being researched.

therapy

The picture shows a standing trainer for children. It is used for therapeutic purposes in children with limited mobility and stability.

There is currently no special therapy or even a cure for BPAN. Treatments are limited to the various symptoms. They include drugs and therapeutic uses.

epilepsy

The forms of epilepsy can vary widely. A patient can also suffer from different types of epilepsy. It is therefore important to properly diagnose the often complex seizure activity and treat it accordingly. This primarily includes medication . Many sufferers report the positive effects of a ketogenic diet , which is also recommended by medical professionals to improve their condition.

Disturbance of language development

The development of spoken language can obviously hardly be influenced. However, those affected benefit from speech therapy , which trains breathing and chewing when eating. Supported communication can help overcome barriers to understanding. Technical aids such as computers can also facilitate the development of communication. However, these approaches are often made more difficult by cognitive impairments, as the patient may first need to be given an understanding of cause and effect. Devices such as a step-by-step can be useful here. Occupational therapy also promotes cognitive development.

Restrictions on movement

Physiotherapy should be used as early as possible. It can improve and promote the mobility of muscles and joints. Depending on the limitation, aids such as walking and standing trainers and orthoses can improve the condition. If cramps persist, botox is sometimes injected into the muscle, which leads to temporary relief from the cramp condition.

Interest groups and self-help groups

The German patient organization Hoffnungsbaum e. V. together with ACHSE e. V. , the umbrella organization for rare diseases , published a patient-oriented description of NBIA in 2017, which contains a few more details and information.

Web links

Literature and individual references

  1. ↑ Beta propeller protein-associated neurodegeneration.  In: Online Mendelian Inheritance in Man . (English)
  2. ^ Susan J. Hayflick, Michael C. Kruer, Allison Gregory, Tobias B. Haack, Manju A. Kurian: Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation . In: Brain . tape 136 , no. 6 , June 1, 2013, ISSN  0006-8950 , p. 1708–1717 , doi : 10.1093 / brain / awt095 , PMID 23687123 , PMC 3673459 (free full text) - ( oup.com [accessed April 28, 2018]).
  3. ↑ Introduction and clinical symptoms. In: NBIA - clinical pictures. Friedrich-Baur-Institut, Klinikum der Universität München, accessed on April 28, 2018 .
  4. ^ Allison Gregory, Susan Hayflick: Neurodegeneration with Brain Iron Accumulation Disorders Overview . In: GeneReviews® . University of Washington, Seattle, Seattle (WA) 2013, PMID 23447832 (English, nih.gov [accessed November 7, 2019]).
  5. ↑ Tobias B. Haack, Penelope Hogarth, Michael C. Kruer, Allison Gregory, Thomas Wieland: Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA . In: The American Journal of Human Genetics . tape 91 , no. 6 , December 2012, ISSN  0002-9297 , p. 1144–1149 , doi : 10.1016 / j.ajhg.2012.10.019 , PMID 23176820 , PMC 3516593 (free full text) - ( elsevier.com [accessed April 28, 2018]).
  6. ↑ Beta-propeller protein-associated neurodegeneration. In: Orphanet.org. Retrieved April 27, 2018 .
  7. ↑ B. Büchner, Friedrich Baur Institute, Hospital of the Ludwig-Maximilians-University of Munich , oral exam. Communication, September 21, 2018.
  8. ↑ WDR45 gene. In: Genetics Home Reference. US National Library of Medicine, accessed May 13, 2018 .
  9. ^ A b c d e Allison Gregory, Manju A. Kurian, Tobias Haack, Susan J. Hayflick, Penelope Hogarth: Beta-Propeller Protein-Associated Neurodegeneration . In: Margaret P. Adam, Holly H. Ardinger, Roberta A. Pagon, Stephanie E. Wallace (Eds.): GeneReviews® [Internet] . University of Washington, February 16, 2017, ISSN  2372-0697 , PMID 28211668 ( nih.gov ).
  10. ↑ Beta-propeller protein-associated neurodegeneration. In: Genetics Home Reference. NIH, US National Library of Medicine, accessed April 27, 2018 .
  11. ↑ Kjersti Eline Stige, Ivar Otto Gjerde, Gunnar Houge, Per Morten Knappskog, Charalampos Tzoulis: Beta-propeller protein-associated neurodegeneration: a case report and review of the literature . In: Clinical Case Reports . tape 6 , no. 2 , January 4, 2018, ISSN  2050-0904 , p. 353-362 , doi : 10.1002 / ccr3.1358 , PMID 29445477 , PMC 5799652 (free full text).
  12. ↑ Yuri A Zarate, Julie R Jones, Melanie A Jones, Francisca Millan, Jane Juusola: Lessons from a pair of siblings with BPAN . In: European Journal of Human Genetics . tape 24 , no. 7 , November 18, 2015, ISSN  1018-4813 , p. 1080-1083 , doi : 10.1038 / ejhg.2015.242 , PMID 26577041 , PMC 5070893 (free full text).
  13. ↑ Ian M. Campbell, Bo Yuan, Caroline Roberecht, Rolph Pfundt, Przemyslaw Szafranski: Parental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders . In: American Journal of Human Genetics . tape 95 , no. 2 , August 7, 2014, ISSN  0002-9297 , p. 173–182 , doi : 10.1016 / j.ajhg.2014.07.003 , PMID 25087610 , PMC 4129404 (free full text).
  14. ↑ Tassula Proikas-Cezanne, Scott Waddell, Anja Gaugel, Tancred Frickey, Andrei Lupas: WIPI-1α (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy . In: Oncogene . tape 23 , no. 58 , December 2004, ISSN  0950-9232 , p. 9314-9325 , doi : 10.1038 / sj.onc.1208331 .
  15. ↑ T. Proikas-Cezanne, Z. Takacs, P. Donne, O. Kohlbacher: WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome . In: Journal of Cell Science . tape 128 , no. 2 , January 15, 2015, ISSN  0021-9533 , p. 207-217 , doi : 10.1242 / jcs.146258 .
  16. ↑ Daniela Bakula, Amelie J. Müller, Theresia Zuleger, Zsuzsanna Takacs, Mirita Franz-Wachtel, Ann-Katrin Thost, Daniel Brigger, Mario P. Tschan, Tancred Frickey, Horst Robenek, Boris Macek & Tassula Proikas-Cezanne: WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signaling circuits in the control of autophagy . In: Nature Communications . tape 8 , May 31, 2017, ISSN  2041-1723 , p. 15637 , doi : 10.1038 / ncomms15637 , PMID 28561066 , PMC 5460038 (free full text).
  17. ↑ Saikat Chowdhury, Chinatsu Otomo, Alexander Leitner, Kazuto Ohashi, Ruedi Aebersold, Gabriel C. Lander, Takanori Otomoa: Insights into autophagosome biogenesis from structural and biochemical analyzes of the ATG2A-WIPI4 complex . In: Proceedings of the National Academy of Sciences of the United States of America . tape 115 , no. 42 , September 5, 2018, ISSN  1091-6490 , p. E9792 – E9801 , doi : 10.1073 / pnas.1811874115 , PMID 30185561 , PMC 6196511 (free full text).
  18. ↑ Takanori Otomo, Saikat Chowdhury, Gabriel C. Lander: The Rod-Shaped ATG2A-WIPI4 Complex Tethers Membranes In Vitro . In: Contact . tape 1 , December 21, 2018, ISSN  2515-2564 , doi : 10.1177 / 2515256418819936 , PMID 30766969 , PMC 6372110 (free full text).
  19. ↑ Shintaro Maeda, Chinatsu Otomo, Takanori Otomo: The autophagic membrane tether ATG2A transfers lipids between membranes . In: eLife . tape 8 , 4th July 2019, ISSN  2050-084X , doi : 10.7554 / eLife.45777 , PMID 31271352 , PMC 6625793 (free full text).
  20. ↑ Philip Seibler, Lena F Burbulla, Marija Dulovic, Simone Zittel, Johanne Heine: Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells . In: Brain . tape 141 , no. 10 , August 30, 2018, ISSN  0006-8950 , p. 3052–3064 , doi : 10.1093 / brain / awy230 ( oup.com [accessed September 28, 2018]).
  21. ↑ Geon Ha Kim, Jieun E. Kim, Sandy Jeong Rhie, Sujung Yoon: The Role of Oxidative Stress in Neurodegenerative Diseases . In: C. Justin Lee, Jong Eun Lee, Byung-Ok Choi (Eds.): Experimental Neurobiology . tape 24 , no. 4 , October 12, 2015, ISSN  1226-2560 , p. 325 , doi : 10.5607 / en.2015.24.4.325 , PMID 26713080 , PMC 4688332 (free full text).
  22. ↑ Finanziato un progetto sulla BPAN: Lena Burbulla studierà il legame tra ferro e neurodegenerazione. In: Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro. August 17, 2019, accessed August 22, 2019 (it-IT).
  23. ↑ Funding of the BPAN project on the connection between iron and neurodegeneration. In: Hoffnungsbaum eV August 21, 2019, accessed on August 22, 2019 (German).
  24. ↑ Petr Dusek, Susanne A. Schneider, Jan Aaseth: Iron chelation in the treatment of neurodegenerative diseases . In: Dirk Schaumlöffel (Ed.): Journal of Trace Elements in Medicine and Biology . tape 38 . Elsevier, December 2016, ISSN  0946-672X , p. 81–92 , doi : 10.1016 / j.jtemb.2016.03.010 ( sciencedirect.com [accessed September 25, 2018]).
  25. ↑ Yuta Ichinose, Michiaki Miwa, Akiko Onohara, Kimiko Obi, Kazumasa Shindo: Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN) . In: Neurology: Clinical Practice . tape 4 , no. 2 , April 1, 2014, ISSN  2163-0402 , p. 175–177 , doi : 10.1212 / 01.CPJ.0000437694.17888.9b , PMID 24790802 , PMC 4001181 (free full text) - ( neurology.org [accessed April 28, 2018]).
  26. ↑ Camilla Russo, Anna Ardissone, Elena Freri, Serena Gasperini, Marco Moscatelli, Giovanna Zorzi, Celeste Panteghini, Barbara Castellotti, Barbara Garavaglia, Nardo Nardocci, Luisa Chiapparini: Substantia Nigra Swelling and Dentate Nucleus T2 Hyperintensity May Be Early Magnetic Imaging Signs of Resonance Imaging β-Propeller Protein-Associated Neurodegeneration: Early MRI Features in 4 Cases of BPAN . In: Kailash Bhatia, Marcelo Merello, International Parkinson and Movement Disorder Society (Eds.): Movement Disorders - Clinical Practice . tape 6 , no. 1 . John Wiley & Sons, Inc., October 10, 2018, p. 51-56 , doi : 10.1002 / mdc3.12693 , PMID 30746416 , PMC 6335537 (free full text).
  27. ↑ BPAN. In: NBIA Disorders. NBIA cure, accessed April 28, 2018 .
  28. ↑ Ketogenic diet effective in resistant epilepsy. (No longer available online.) In: aerzteblatt.de. Deutscher Ärzteverlag GmbH, May 8, 2008, archived from the original on May 1, 2018 ; accessed on April 30, 2018 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.aerzteblatt.de
  29. ↑ Elizabeth G Neal, Hannah Chaffe, Ruby H Schwartz, Margaret S Lawson, Nicole Edwards: The ketogenic diet for the treatment of childhood epilepsy: a randomized controlled trial . In: The Lancet Neurology . tape 7 , no. 6 , June 2008, ISSN  1474-4422 , p. 500-506 , doi : 10.1016 / s1474-4422 (08) 70092-9 .
  30. ↑ Eunjoo Lee, Hoon-Chul Kang, Heung Dong Kim: Ketogenic Diet for Children with Epilepsy: A Practical Meal Plan in a Hospital . In: Clinical Nutrition Research . tape 5 , no. 1 , 2016, ISSN  2287-3732 , p. 60 , doi : 10.7762 / cnr.2016.5.1.60 , PMID 26839878 , PMC 4731863 (free full text).
  31. ↑ Botulinum toxin (injection therapy). Deutsche Dystonie Gesellschaft eV, accessed on January 27, 2019 .