Neural ceroid lipofuscinosis

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Classification according to ICD-10
E75.4 Neural ceroid lipofuscinosis
ICD-10 online (WHO version 2019)

The neuronal ceroid lipofuscinosis (NCL or CLN), also known as VSS or outdated as amaurotic idiocy , are a group of rare, inherited and so far incurable metabolic diseases that can occur in different forms and ages. They belong to the group of lysosomal storage diseases . Colloquially , NCL is referred to as child dementia .

The term N euro-dimensional C eroid- L ipofuszinosen (NCL) is derived from:

Common characteristics are progressive mental deterioration, epilepsy and degeneration of the retina . It is based on the deposition of ceroid lipofuscin in the brain and retina .

Frequency and inheritance

Most forms are autosomal - recessive inherited, only the adult form CLN4 is autosomal dominant passed.

The disease usually occurs between the ages of 1 and 8 years with a maximum incidence rate of 1 in 30,000 live births.

Clinical picture

Histological evidence of the strong purple colored degradation products in the nerve cells ( PAS )

The pathophysiology of NCL is still largely unknown. It is certain that in all forms the waxy ceroid lipofuscins - waste materials from cell metabolism consisting of fats and proteins - are stored intracellularly in the tissue. This makes the cell climate toxic, which leads to the death of healthy cells.

Initially, the disease manifests itself through increasing visual impairment, which eventually leads to complete blindness due to damage to the retina (retinopathy). Associated with this, hallucinations , epilepsy and dementia occur in those affected . Ultimately, the patient loses all cognitive and motor skills. In the past, every form of NCL inevitably led to death and only palliative treatment methods were possible. Since May 2017, drug therapy has been available that can at least stop the progression of the disease in a high percentage of cases.

Classification

In the past, the classification of the NCL types was based on the age of manifestation , and terms such as infantile , late infantile or juvenile NCL were used accordingly . In the meantime 10 NCL types (CLN1-CLN10) are known, whereby the types CLN1 and CLN4 can only appear in adulthood.

The modern classification takes place on a genetic basis, the numbering of the individual types (CLN1, CLN2 etc.) takes place according to the historical order of the discovery.

Type designation Age of manifestation root cause other name (s)
CLN1 infantile NCL late infancy, including adulthood Mutations in the PPT1 / CLN1 gene at location 1p32 (for lysosomal palmitoyl protein thioesterase) Hagberg-Santavuori disease
CLN2 (classical) late infantile NCL Toddler age Mutations in the TPP1 gene at location 11p15.4 Jansky-Bielschowsky disease, Bielschowsky's amaurotic idiocy, Bernheimer-Seitelberger syndrome, Dollinger-Bielschowsky syndrome
CLN3 (classic) juvenile NCL School age Mutations in the CLN3 gene at location 16p11.2 Stengel's disease, Vogt-Spielmeyer-Stock disease (VSS), Batten disease, Batten disease
CLN4 adult NCL (autosomal recessive or dominant) Adulthood Mutations in the genes PPT1 / CLN1 at location 1p32 or CTSD / CLN10 at location 11p15.5 Kufs syndrome, Batten-Kufs syndrome
CLN5 (Finnish) late infantile NCL Toddler age various mutations Mutations in the CLN5 gene at location 13q22.3
CLN6 Indo-Iberian NCL Toddler age Mutations in the CLN6 gene at location 15q23
CLN7 Turkish NCL Toddler age Mutations in the MFSD8 gene at location 4q28.2
CLN8 nordic epilepsy School age Mutations in the CLN8 gene at location 8p23.3 Northern epilepsy; Epilepsy, Progressive, With Mental Retardation; EPMR
CLN9 Occurring in Germany and Serbia School age
CLN10 congenital CLN Newborn Infant Age Mutations in the CTSD / CLN10 gene at location 11p15.5 (lysosomal protease Cathepsin D) Norman Wood Syndrome

Diagnosis

The diagnosis results from the clinical including the ophthalmological examination and is confirmed by genetic tests. As Imaging method of choice today is considered MRI . This documents an atrophy of the cerebrum and cerebellum , T2 signal increases in white matter and thinning of the cerebral cortex.

Drug therapy

The biotechnologically produced recombinant tripeptidyl-peptidase-1 cerliponase alfa can replace the enzyme missing in CLN2 by being introduced into the CSF space via a catheter every 14 days (solution for intracerebroventricular infusion). It was approved as a medicinal product in the European Union on May 30, 2017 under the name "Brineura". As part of a compassionate use program , the Federal Institute for Drugs and Medical Devices had already approved marketing for the treatment of patients with neuronal ceroid lipofuscinosis type 2 (CLN2, tripeptidyl peptidase 1 (TPP 1) deficiency) in July 2016.
In an international, multicenter study, the course of the disease was completely halted in around two thirds of childhood patients. The therapy costs are currently (2018) € 750,000 per year. In Great Britain, the assumption of costs is rejected on the grounds that it is too costly in relation to the benefits.

history

The disease was first described in 1826 by the Norwegian country doctor Stengel on the basis of four siblings and was called Stengel's disease until 1903 . Later, the designation Batten disease (still known today in English-speaking countries as batten disease ) and Vogt-Spielmeyer-Stock disease (VSS, still used in Germany today) were common. It was proven in 1939 that it was a metabolic disease. In 1963, the name Ceroid Lipofuscin Pigment was coined for the fats and proteins that accumulate in the cells as waste materials . In 1995 it was found out that a genetic defect - namely the loss of a chromosome segment  - is the cause of the disease. It has been known since 1998 that those affected lack a lysosomal enzyme , which is required to break down waste materials in the cells .

See also

literature

  • Kurt Kallenbach (ed.): Children with special needs. Selected clinical pictures and forms of disability ( ISBN 3-89166-208-4 )
  • Alfried Kohlschütter, Hans-Hilmar Goebel, Angela Schulz, Zoltan Lukacs: The neuronal ceroid lipofuscinoses. Dementia in children and adolescents . In: Deutsches Ärzteblatt , issue 5, February 2005
  • MN Preising, B. Lorenz: Genetics of the neuronal ceroid lipofuscinoses . In: Der Ophthalmologe: Journal of the German Ophthalmological Society. Volume 107, No. 7, July 2010, pp. 612-615, doi: 10.1007 / s00347-009-2107-x , PMID 20532525 (review).

Web links

Individual evidence

  1. ↑ Neuronal ceroid lipofuscinosis. In: Orphanet (Rare Disease Database).
  2. ^ The neuronal ceroid lipofuscinoses
  3. ↑ a b Angela Schulz et al .: Study of Intraventricular Cerliponase Alfa for CLN2 Disease . In: New England Journal of Medicine , 2018; Accessed April 25, 2018. doi: 10.1056 / NEJMoa1712649
  4. ↑ CLN1. In: Orphanet (Rare Disease Database).
  5. ↑ CLN2.  In: Online Mendelian Inheritance in Man . (English)
  6. ↑ NCBI: TPP1 tripeptidyl peptidase I . Retrieved December 13, 2016.
  7. ↑ CLN3. In: Orphanet (Rare Disease Database).
  8. ↑ CLN3.  In: Online Mendelian Inheritance in Man . (English)
  9. ↑ CLN4. In: Orphanet (Rare Disease Database).
  10. ↑ CLN5. In: Orphanet (Rare Disease Database).
  11. ↑ CLN5.  In: Online Mendelian Inheritance in Man . (English)
  12. ↑ CLN6.  In: Online Mendelian Inheritance in Man . (English)
  13. ↑ CLN7.  In: Online Mendelian Inheritance in Man . (English)
  14. ↑ CLN8.  In: Online Mendelian Inheritance in Man . (English)
  15. ↑ CLN9.  In: Online Mendelian Inheritance in Man . (English)
  16. ↑ CLN10. In: Orphanet (Rare Disease Database).
  17. ^ RM Norman, N. Wood: A Congenital Form of Amaurotic Family Idiocy. In: Journal of neurology and psychiatry. Volume 4, Number 3-4, July 1941, pp. 175-190, PMID 21611390 , PMC 1089784 (free full text).
  18. ↑ L. D'Incerti: MRI in neuronal ceroid lipofuscinosis. In: Neurological sciences: official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. Vol. 21, No. 3 Suppl, 2000, pp. S71-S73, PMID 11073231 (review).
  19. ↑ Entry on cerliponase alfa in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on November 17, 2019.
  20. ↑ Gene therapy for Batten's disease achieves initial success in dogs. In: aerzteblatt.de . November 12, 2015, accessed November 17, 2019 .
  21. ^ Find medicine. European Medicines Agency, accessed July 4, 2017 .
  22. ↑ Compassionate use programs. ( Memento of the original from November 8, 2017 in the Internet Archive ) 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. Federal Institute for Drugs and Medical Devices . Retrieved December 13, 2016. @1@ 2Template: Webachiv / IABot / www.bfarm.de
  23. ^ Rainer Woratschka: Up to 750,000 euros per patient. The rise in drug prices alarms health insurance companies. In: www.tagesspiegel.de. DER TAGESSPIEGEL, accessed on October 30, 2018 .
  24. ↑ Evaluation consultation document: Cerliponase alfa for treating neuronal ceroid lipofuscinosis type 2 . NICE . Retrieved August 9, 2018.
  25. ↑ NICE deems Batten disease therapy too costly for NHS use . In: Pharma Times , February 13, 2018. Retrieved August 9, 2018.