Canavan's disease

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The Canavan disease is one of the genetically caused leukodystrophies . Due to the degeneration of the white matter , the brain swells and the myelin becomes spongy, which is why it is sometimes referred to as spongy degeneration of the nervous system .

The neurodegenerative disease was named after Myrtelle Canavan , who described this disease in 1931 - assuming Schilder's disease. A mutation on the short arm of chromosome 17 is responsible .

Epidemiology

Canavan disease is inherited as an autosomal - recessive trait . The disease occurs in all ethnic groups, but it is more common among Ashkenazi Jewish people and Arab people from Saudi Arabia .

clinic

The affected children are normal at birth . In the most common infantile form, the first symptoms appear between the 3rd and 9th month of life. The children are conspicuous by regressions in psychomotor development (lack of head control, muscular hypotension ) and macrocephalus .

In the course of the disease, the children mainly show a disorder of motor development. The children are not able to sit, stand, run or speak freely. Other neurological symptoms are spastic paralysis , cerebral seizures, and swallowing disorders . In addition, there is optical atrophy , which greatly reduces vision but does not necessarily lead to blindness.

In addition to the infantile form, there are also the following forms:

  • Congenital Canavan disease: symptoms appear from birth; life expectancy is a few days or weeks
  • juvenile Canavan disease: delayed appearance of symptoms and slower progression; the patients often survive into the second decade of life

With good medical and nursing care, children can now reach teenage years.

root cause

The disease is based on a genetic deficiency of the enzyme asparto acylase , which occurs exclusively in the brain and is supposed to break down N-acetylaspartate (NAA; N-acetylaspartic acid) there. The aggregation of NAA leads to cancellous changes and swelling of the brain. It also damages the white matter in the brain. More precisely, myelin is lost, which means that the transfer of information between the individual brain regions no longer works. The functional impairment of the neurons is secondary to the loss of myelin.

The mutations that lead to the disease are in the ASPA gene, which is located on the short arm of chromosome 17 and codes for the enzyme aspartoacylase.

diagnosis

The white matter disorder can be detected by a skull magnetic resonance imaging (MRI) scan. Typical findings are:

In terms of differential diagnosis , maple syrup disease is mainly to be differentiated on the MRI .

The diagnosis is confirmed by the detection of greatly increased NAA in the urine . This test is specific for Canavan disease and is sufficient as a diagnosis. Alternatively, the activity of asparto acylase in cultured skin cells can be determined. Furthermore, can the molecular genetic studies of the ASPA gene are performed.

In cases of Canavan disease in the family, prenatal diagnostics can also be carried out for a further pregnancy . The most common causative mutations can be detected by an amniocentesis or a chorionic villus sampling in the case of the disease. Even if there is no specific mutation in the DNA , the diagnosis of Canavan's disease can be made by an increased NAA concentration in the amniotic fluid.

therapy

There is currently no way to treat the cause of the disease. So only supportive measures can be taken.

However, attempts have been made for several years to cure the disease using gene therapy. An attempt is being made to introduce the missing ASPA gene into the brain using a viral gene ferry using adenoviruses. This allowed the concentration of N-acetyl aspartate to be reduced in the animal model, but the white substance remained cancellous. An improved gene ferry and earlier application did not bring satisfactory results either.

swell

  • Georg Friedrich Hoffman: Metabolic diseases in neurology. Thieme, Stuttgart / New York 2004, ISBN 3-13-136321-5 , p. 23f.

Web links

Individual evidence

  1. ↑ Canavan MM. Schilder's encephalitis periaxialis diffusa. Report of a case in a child aged sixteen and one-half months. Arch Neurol Psychiatry 1931; 25: 299-308
  2. ↑ NINDS Canavan Disease Information Page ( Memento of the original from January 24, 2005 in the Internet Archive ) Info: The archive link has been 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.ninds.nih.gov
  3. ↑ Shalini Kumar, Natalia S. Mattan, Jean de Vellis: Canavan disease: A white matter disorder. In: Mental Retardation and Developmental Disabilities Research Reviews. 12, 2006, pp. 157-165, doi: 10.1002 / mrdd.20108 .
  4. ↑ M van derKnaap, J Valk: Magnetic Resonance of Myeliation and Myelin Disorders, Springer 2005, ISBN 3-540-22286-3 .
  5. ↑ P. Leone, CG Janson, L. Bilaniuk, Z. Wang, F. Sorgi, L. Huang, R. Matalon, R. Kaul, Z. Zeng, A. Freese, SW McPhee, E. Mee, MJ During, L. Bilianuk: Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. In: Annals of neurology. Volume 48, Number 1, July 2000, pp. 27-38, ISSN  0364-5134 . PMID 10894213 .
  6. ↑ Christopher Janson, Scott McPhee, Larissa Bilaniuk, John Haselgrove, Mark Testaiuti, Andrew Freese, Dah-Jyuu Wang, David Shera, Peter Hurh, Joan Rupin, Elizabeth Saslow, Olga Goldfarb, Michael Goldberg, Ghassem Larijani, William Sharrar, Larisa Liouterman , Angelique Camp, Edwin Kolodny, Jude Samulski, Paola Leone: Gene Therapy of Canavan Disease: AAV-2 Vector for Neurosurgical Delivery of Aspartoacylase Gene () to the Human Brain. In: Human Gene Therapy. 13, 2002, pp. 1391-1412, doi: 10.1089 / 104303402760128612 .
  7. ^ R. Matalon, S. Surendran, PL Rady, MJ Quast, GA Campbell, KM Matalon, SK Tyring, J. Wei, CS Peden, EL Ezell, N. Muzyczka, RJ Mandel: Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease. In: Molecular therapy: the journal of the American Society of Gene Therapy. Volume 7, Number 5 Pt 1, May 2003, pp. 580-587, ISSN  1525-0016 . PMID 12718900 .
  8. ↑ SWJ McPhee, J. .. Francis, CG Janson, T. .. Serikawa, K. .. Hyland, EO Ong, SS Raghavan, A. .. Freese, P. .. Leone: Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease. In: Molecular Brain Research. 135, 2005, pp. 112-121, doi: 10.1016 / j.molbrainres . 2004.12.007 .
  9. ↑ M. KLUGMANN, C. LEICHTLEIN, C. SYMES, T. SERIKAWA, D. YOUNG, M. DURING: Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease. In: Molecular Therapy. 11, 2005, pp. 745-753, doi: 10.1016 / j.ymthe.2005.01.006 .